{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:50:48Z","timestamp":1791921048961,"version":"4.3.4"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T00:00:00Z","timestamp":1615420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Endocrine therapy represents the cornerstone of treatment in hormone receptor-positive (HR+), HER2-negative metastatic breast cancer (mBC). The natural course of this disease is marked by endocrine resistance, mainly due to Estrogen Receptor 1 (ESR1) acquired mutations. The aim of this study is to evaluate the concordance between ESR1 status in metastatic tumor specimens and matched circulating tumor DNA (ctDNA). Forty-three patients with HR+, HER2-negative mBC underwent both a metastatic tumor biopsy and a liquid biopsy at the time of disease progression. DNA extracted from formalin fixed paraffin embedded (FFPE) tumor specimens and ctDNA from matched plasma were analyzed by droplet digital (dd)PCR for the main ESR1 mutations (Y537S, Y537C, Y537N, D538G, E380Q). We observed a total mutation rate of 21%. We found six mutations on tissue biopsy: Y537S (1), D538G (2), Y537N (1), E380Q (2). Three patients with no mutations in tumor tissue had mutations detected in ctDNA. The total concordance rate between ESR1 status on tumor tissue and plasma was 91%. Our results confirm the potential role of liquid biopsy as a non-invasive alternative to tissue biopsy for ESR1 mutation assessment in mBC patients.<\/jats:p>","DOI":"10.3389\/fonc.2021.625636","type":"journal-article","created":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T06:46:35Z","timestamp":1615445195000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["ESR1 Gene Mutation in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer Patients: Concordance Between Tumor Tissue and Circulating Tumor DNA Analysis"],"prefix":"10.3389","volume":"11","author":[{"given":"Loredana","family":"Urso","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grazia","family":"Vernaci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Carlet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Lo Mele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Fassan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Zulato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Faggioni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Menichetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Di Liso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaia","family":"Griguolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Falci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierfranco","family":"Conte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Indraccolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Guarneri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Vittoria","family":"Dieci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"87","DOI":"10.3322\/caac.21262","article-title":"Global cancer statistics, 2012","volume":"65","author":"Torre","year":"2015","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.67.1487","article-title":"Endocrine Therapy for Hormone Receptor-Positive Metastatic Breast Cancer: American Society of Clinical Oncology Guideline","volume":"34","author":"Rugo","year":"2016","journal-title":"J Clin Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(19801215)46:12+<2835::AID-CNCR2820461420>3.0.CO;2-M","article-title":"The problem of nonresponding estrogen receptor-positive patients with advanced breast cancer","volume":"46","author":"Maass","year":"1980","journal-title":"Cancer"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2015.117","article-title":"ESR1 mutations-a mechanism for acquired endocrine resistance in breast cancer","volume":"12","author":"Jeselsohn","year":"2015","journal-title":"Nat Rev Clin Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)41801-1","article-title":"Phosphorylation of the human estrogen receptor. Identification of hormone-regulated sites and examination of their influence on transcriptional activity","volume":"269","author":"Le Goff","year":"1994","journal-title":"J Biol Chem"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/29.14.2905","article-title":"Estrogen receptor interaction with estrogen response elements","volume":"29","author":"Klinge","year":"2001","journal-title":"Nucleic Acids Res"},{"key":"B7","article-title":"Breast cancer endocrine resistance: how growth factor signaling and estrogen receptor coregulators modulate response","volume":"9","author":"Schiff","year":"2003","journal-title":"Clin Cancer Res"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1677\/erc.0.0060373","article-title":"Involvement of steroid hormone and growth factor cross-talk in endocrine response in breast cancer","volume":"6","author":"Nicholson","year":"1999","journal-title":"Endocr Relat Cancer"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/nrc721","article-title":"Endocrine-responsive breast cancer and strategies for combating resistance","volume":"2","author":"Ali","year":"2002","journal-title":"Nat Rev Cancer"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1997.7124","article-title":"Regulation of Cre recombinase activity by mutated estrogen receptor ligand-binding domains","volume":"237","author":"Feil","year":"1997","journal-title":"Biochem Biophys Res Commun"},{"key":"B11","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1158\/1078-0432.CCR-14-0067","article-title":"Estrogen Receptor Mutations in Breast Cancer\u2014New Focus on an Old Target","volume":"2014","author":"Segal","year":"2014","journal-title":"Clin Cancer Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2823","article-title":"Activating ESR1 mutations in hormone-resistant metastatic breast cancer","volume":"45","author":"Robinson","year":"2013","journal-title":"Nat Genet"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2822","article-title":"ESR1 ligand- binding domain mutations in hormone-resistant breast cancer","volume":"45","author":"Toy","year":"2013","journal-title":"Nat Genet"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-2332","article-title":"Emergence of constitutively active estrogen receptor-alpha mutations in pretreated advanced estrogen receptor-positive breast cancer","volume":"20","author":"Jeselsohn","year":"2014","journal-title":"Clin Cancer Res"},{"key":"B15","doi-asserted-by":"publisher","first-page":"313ra182","DOI":"10.1126\/scitranslmed.aac7551","article-title":"Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer","volume":"7","author":"Schiavon","year":"2015","journal-title":"Sci Transl Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2017.00026","article-title":"Clinical Implications of ESR1 Mutations in Hormone Receptor-Positive Advanced Breast Cancer","volume":"7","author":"Reinert","year":"2017","journal-title":"Front Oncol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.67.3061","article-title":"Plasma ESR1 Mutations and the Treatment of Estrogen Receptor-Positive Advanced Breast Cancer","volume":"34","author":"Fribbens","year":"2016","journal-title":"J Clin Oncol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1016\/j.ccell.2018.08.008","article-title":"The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers","volume":"34","author":"Razavi","year":"2018","journal-title":"Cancer Cell"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-1197","article-title":"D538G mutation in estrogen receptor-\u03b1: A novel mechanism for R.; Brown, M.; Miller, V.A.; Sarid, D.; et al. D538G mutation in estrogen receptor-\u03b1: A novel mechanism for acquired endocrine resistance in breast cancer","volume":"73","author":"Merenbakh-Lamin","year":"2013","journal-title":"Cancer Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-0224","article-title":"ESR1 Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor\u2013Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trials","author":"Turner","year":"2020","journal-title":"Clin Cancer Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-2357","article-title":"AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive and ESR1-Mutant Breast Tumors in Preclinical Models","volume":"76","author":"Weir","year":"2016","journal-title":"Cancer Res"},{"key":"B22","doi-asserted-by":"publisher","first-page":"10.7554\/eLife.15828","DOI":"10.7554\/eLife.44851","article-title":"The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer","volume":"5","author":"Joseph","year":"2016","journal-title":"Elife"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-2561","article-title":"Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER(+) Breast Cancer Patient-derived Xenograft Models","volume":"23","author":"Bihani","year":"2017","journal-title":"Clin Cancer Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1097\/CAD.0000000000000271","article-title":"RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models","volume":"26","author":"Garner","year":"2015","journal-title":"Anticancer Drugs"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2019.01.006","article-title":"Liquid Biopsies in Cancer Diagnosis, Monitoring, and Prognosis","volume":"40","author":"De Rubis","year":"2019","journal-title":"Trends Pharmacol Sci"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2015.238717","article-title":"Noninvasive detection of activating estrogen receptor 1 (ESR1) mutations in estrogen receptor-positive metastatic breast cancer","volume":"61","author":"Guttery","year":"2015","journal-title":"Clin Chem"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2016.1279","article-title":"Prevalence of ESR1 Mutations in Cell-Free DNA and Outcomes in Metastatic Breast Cancer: A Secondary Analysis of the BOLERO-2 Clinical Trial","volume":"2","author":"Chandarlapaty","year":"2016","journal-title":"JAMA Oncol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-020-1174-y","article-title":"A single droplet digital PCR for ESR1 activating mutations detection in plasma","volume":"39","author":"Jeannot","year":"2020","journal-title":"Oncogene"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2017.07.004","article-title":"Comparison of ESR1 Mutations in Tumor Tissue and Matched Plasma Samples from Metastatic Breast Cancer Patients","volume":"10","author":"Takeshita","year":"2017","journal-title":"Transl Oncol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-0943","article-title":"ESR1 Mutations in Circulating Plasma Tumor DNA from Metastatic Breast Cancer Patients","volume":"22","author":"Chu","year":"2016","journal-title":"Clin Cancer Res"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0196434","article-title":"Formalin fixation increases deamination mutation signature but should not lead to false positive mutations in clinical practice","volume":"13","author":"Prentice","year":"2018","journal-title":"PloS One"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-017-4190-z","article-title":"Detection of ESR1 mutations in plasma and tumors from metastatic breast cancer patients using next-generation sequencing","volume":"163","author":"Yanagawa","year":"2017","journal-title":"Breast Cancer Res Treat"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.29612","article-title":"Short report: Monitoring ESR1 mutations by circulating tumor DNA in aromatase inhibitor resistant metastatic breast cancer","volume":"137","author":"Sefrioui","year":"2015","journal-title":"Int J Cancer"},{"key":"B34","doi-asserted-by":"publisher","first-page":"4371","DOI":"10.1038\/s41598-018-22312-x","article-title":"High-sensitivity assay for monitoring ESR1 mutations in circulating cell-free DNA of breast cancer patients receiving endocrine therapy","volume":"8","author":"Lupini","year":"2018","journal-title":"Sci Rep"},{"key":"B35","doi-asserted-by":"publisher","first-page":"11579","DOI":"10.1038\/ncomms11579","article-title":"Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant","volume":"7","author":"Spoerke","year":"2016","journal-title":"Nat Commun"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-1534","article-title":"Sensitive Detection of Mono- and Polyclonal ESR1 Mutations in Primary Tumors, Metastatic Lesions, and Cell-Free DNA of Breast Cancer Patients","volume":"22","author":"Wang","year":"2016","journal-title":"Clin Cancer Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.2147\/CMAR.S173193","article-title":"Clinical value of circulating ESR1 mutations for patients with metastatic breast cancer: a meta-analysis","volume":"10","author":"Zhang","year":"2018","journal-title":"Cancer Manag Res"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.625636\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T06:46:40Z","timestamp":1615445200000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.625636\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,11]]},"references-count":37,"alternative-id":["10.3389\/fonc.2021.625636"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2021.625636","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,11]]},"article-number":"625636"}}