{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T11:41:10Z","timestamp":1792669270170,"version":"4.5.0"},"reference-count":68,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T00:00:00Z","timestamp":1792627200000},"content-version":"vor","delay-in-days":30,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Plasma cell-free DNA (cfDNA) is a sensitive, noninvasive tool for monitoring the genomic landscape, heterogeneity, and evolution of cancer, aggregating genetic information from multiple metastatic sites. Here, we study 15,564 cfDNA samples from 12,827 patients with metastatic breast cancer (MBC). We classify samples, deep-sequenced with Guardant360, into MBC subtypes using our trained random forest model. Most patients have variants associated with therapeutic resistance and targetability of approved and experimental therapies, including in\u00a0\n                    <jats:italic>PIK3CA, ESR1, PTEN<\/jats:italic>\n                    , and\n                    <jats:italic>AKT1<\/jats:italic>\n                    . Frequencies of multiple actionable alterations differed from primary disease, and multiple variants per gene suggest independent resistant clones. The\u00a0large cohort size enables\u00a0uncovering clonal co-behaviors, including co-existence and exclusivity of alleles and correlation of allele fractions. cfDNA testing is now recommended in multiple advanced malignancies, including eligibility assessment for clinical trials. We envision this large collection of MBC cfDNA data as an invaluable resource for the design and planning of future clinical trials.\n                  <\/jats:p>","DOI":"10.1038\/s41467-026-75976-9","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:36:56Z","timestamp":1790077016000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Actionable genetic landscape and dynamics in circulating DNA from 12,827 patients with metastatic breast cancer"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8942-9265","authenticated-orcid":false,"given":"Ignaty","family":"Leshchiner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arielle J.","family":"Medford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6026-2211","authenticated-orcid":false,"given":"Justin","family":"Cha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5081-2005","authenticated-orcid":false,"given":"Lesli A.","family":"Kiedrowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrzej","family":"Niemierko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer C.","family":"Keenan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles S.","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8904-3514","authenticated-orcid":false,"given":"Laura M.","family":"Spring","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3472-1140","authenticated-orcid":false,"given":"Beverly","family":"Moy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth A.","family":"Wander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neelima","family":"Vidula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6677-1014","authenticated-orcid":false,"given":"Steven J.","family":"Isakoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2983-7704","authenticated-orcid":false,"given":"Dejan","family":"Juric","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mendy","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew A.","family":"Davis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Gerratana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ami","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8119-2291","authenticated-orcid":false,"given":"Ben H.","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8080-7960","authenticated-orcid":false,"given":"Adam","family":"Brufsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce","family":"O\u2019Shaughnessy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca J.","family":"Nagy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0444-7910","authenticated-orcid":false,"given":"Leif W.","family":"Ellisen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Cristofanilli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4885-1157","authenticated-orcid":false,"given":"Aditya","family":"Bardia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0936-0753","authenticated-orcid":false,"given":"Gad","family":"Getz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"75976_CR1","first-page":"7","volume":"70","author":"RL Siegel","year":"2020","unstructured":"Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin. 70, 7\u201330 (2020).","journal-title":"CA Cancer J. Clin."},{"key":"75976_CR2","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1038\/s41588-018-0287-5","volume":"51","author":"U Nayar","year":"2019","unstructured":"Nayar, U. et al. Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor-directed therapies. Nat. Genet. 51, 207\u2013216 (2019).","journal-title":"Nat. Genet."},{"key":"75976_CR3","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1158\/1078-0432.CCR-18-4044","volume":"26","author":"A Pearson","year":"2020","unstructured":"Pearson, A. et al. Inactivating NF1 mutations are enriched in advanced breast cancer and contribute to endocrine therapy resistance. Clin. Cancer Res. 26, 608\u2013622 (2020).","journal-title":"Clin. Cancer Res."},{"key":"75976_CR4","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1038\/s41586-019-1056-z","volume":"569","author":"F Bertucci","year":"2019","unstructured":"Bertucci, F. et al. Genomic characterization of metastatic breast cancers. Nature 569, 560\u2013564 (2019).","journal-title":"Nature"},{"key":"75976_CR5","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/nature11154","volume":"486","author":"S Banerji","year":"2012","unstructured":"Banerji, S. et al. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 486, 405\u2013409 (2012).","journal-title":"Nature"},{"key":"75976_CR6","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1038\/nature11412","volume":"490","author":"N Cancer Genome Atlas","year":"2012","unstructured":"Cancer Genome Atlas, N. Comprehensive molecular portraits of human breast tumours. Nature 490, 61\u201370 (2012).","journal-title":"Nature"},{"key":"75976_CR7","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1016\/j.cell.2015.09.033","volume":"163","author":"G Ciriello","year":"2015","unstructured":"Ciriello, G. et al. Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer. Cell 163, 506\u2013519 (2015).","journal-title":"Cell"},{"key":"75976_CR8","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1038\/nature11143","volume":"486","author":"MJ Ellis","year":"2012","unstructured":"Ellis, M. J. et al. Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature 486, 353\u2013360 (2012).","journal-title":"Nature"},{"key":"75976_CR9","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/nature17676","volume":"534","author":"S Nik-Zainal","year":"2016","unstructured":"Nik-Zainal, S. et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 534, 47\u201354 (2016).","journal-title":"Nature"},{"key":"75976_CR10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/ncomms11479","volume":"7","author":"B Pereira","year":"2016","unstructured":"Pereira, B. et al. The somatic mutation profiles of 2433 breast cancers refine their genomic and transcriptomic landscapes. Nat. Commun. 7, 1\u201316 (2016).","journal-title":"Nat. Commun."},{"key":"75976_CR11","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1038\/nature10933","volume":"486","author":"SP Shah","year":"2012","unstructured":"Shah, S. P. et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 486, 395\u2013399 (2012).","journal-title":"Nature"},{"key":"75976_CR12","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1038\/nature11017","volume":"486","author":"PJ Stephens","year":"2012","unstructured":"Stephens, P. J. et al. The landscape of cancer genes and mutational processes in breast cancer. Nature 486, 400\u2013404 (2012).","journal-title":"Nature"},{"key":"75976_CR13","doi-asserted-by":"publisher","first-page":"3528","DOI":"10.1158\/1078-0432.CCR-17-3837","volume":"24","author":"OA Zill","year":"2018","unstructured":"Zill, O. A. et al. The landscape of actionable genomic alterations in cell-free circulating tumor DNA from 21,807 advanced cancer patients. Clin. Cancer Res. 24, 3528\u20133538 (2018).","journal-title":"Clin. Cancer Res."},{"key":"75976_CR14","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1038\/s41571-019-0187-3","volume":"16","author":"K Pantel","year":"2019","unstructured":"Pantel, K. & Alix-Panabi\u00e8res, C. Liquid biopsy and minimal residual disease - latest advances and implications for cure. Nat. Rev. Clin. Oncol. 16, 409\u2013424 (2019).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"75976_CR15","doi-asserted-by":"publisher","first-page":"1296","DOI":"10.1016\/S1470-2045(20)30444-7","volume":"21","author":"NC Turner","year":"2020","unstructured":"Turner, N. C. et al. Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial. Lancet Oncol. 21, 1296\u20131308 (2020).","journal-title":"Lancet Oncol."},{"key":"75976_CR16","doi-asserted-by":"publisher","first-page":"3404","DOI":"10.1158\/1078-0432.CCR-20-3444","volume":"27","author":"N Vidula","year":"2021","unstructured":"Vidula, N. et al. Tumor tissue- versus plasma-based genotyping for selection of matched therapy and impact on clinical outcomes in patients with metastatic breast cancer. Clin. Cancer Res. 27, 3404\u20133413 (2021).","journal-title":"Clin. Cancer Res."},{"key":"75976_CR17","doi-asserted-by":"publisher","first-page":"5172","DOI":"10.1158\/1078-0432.CCR-20-0224","volume":"26","author":"NC Turner","year":"2020","unstructured":"Turner, N. C. et al. ESR1 mutations and overall survival on fulvestrant versus exemestane in advanced hormone receptor-positive breast cancer: a combined analysis of the phase III SoFEA and EFECT trials. Clin. Cancer Res. 26, 5172\u20135177 (2020).","journal-title":"Clin. Cancer Res."},{"key":"75976_CR18","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1038\/nrclinonc.2015.117","volume":"12","author":"R Jeselsohn","year":"2015","unstructured":"Jeselsohn, R., Buchwalter, G., De Angelis, C., Brown, M. & Schiff, R. ESR1 mutations\u2014a mechanism for acquired endocrine resistance in breast cancer. Nat. Rev. Clin. Oncol. 12, 573\u2013583 (2015).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"75976_CR19","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1038\/ng.2822","volume":"45","author":"W Toy","year":"2013","unstructured":"Toy, W. et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat. Genet. 45, 1439\u20131445 (2013).","journal-title":"Nat. Genet."},{"key":"75976_CR20","doi-asserted-by":"crossref","unstructured":"Chakravarty, D. et al. Somatic genomic testing in patients with metastatic or advanced cancer: ASCO provisional clinical opinion. J. Clin. Oncol. 40, 1231\u20131258 (2022).","DOI":"10.1200\/JCO.21.02767"},{"key":"75976_CR21","doi-asserted-by":"crossref","unstructured":"Henry, N. L. et al. Biomarkers for systemic therapy in metastatic breast cancer: ASCO guideline update. J. Clin. Oncol. 40, 3205\u20133221 (2022).","DOI":"10.1200\/JCO.22.01063"},{"key":"75976_CR22","doi-asserted-by":"crossref","unstructured":"Burstein, H. J. et al. Testing for ESR1 Mutations to Guide Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update. J. Clin. Oncol. 41, 3423\u20133425 (2023).","DOI":"10.1200\/JCO.23.00638"},{"key":"75976_CR23","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1038\/nature10983","volume":"486","author":"C Curtis","year":"2012","unstructured":"Curtis, C. et al. The genomic and transcriptomic architecture of 2000 breast tumours reveals novel subgroups. Nature 486, 346\u2013352 (2012).","journal-title":"Nature"},{"key":"75976_CR24","doi-asserted-by":"crossref","unstructured":"Aftimos, P. et al. Genomic and transcriptomic analyses of breast cancer primaries and matched metastases in AURORA, the Breast International Group (BIG) molecular screening initiative. Cancer Discov. 11, 2796\u20132811 (2021).","DOI":"10.1158\/2159-8290.CD-20-1647"},{"key":"75976_CR25","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1016\/j.ccell.2018.08.008","volume":"34","author":"P Razavi","year":"2018","unstructured":"Razavi, P. et al. The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers. Cancer Cell 34, 427\u2013438.e426 (2018).","journal-title":"Cancer Cell"},{"key":"75976_CR26","unstructured":"Garcia-Recio et al. Multiomics in primary and metastatic breast tumors from the AURORA US network finds microenvironment and epigenetic drivers of metastasis. Nat. Cancer 4, 128\u2013147 (2023)."},{"key":"75976_CR27","doi-asserted-by":"publisher","first-page":"1881","DOI":"10.1038\/bjc.2014.341","volume":"111","author":"D Zardavas","year":"2014","unstructured":"Zardavas, D. et al. The AURORA initiative for metastatic breast cancer. Br. J. Cancer 111, 1881\u20131887 (2014).","journal-title":"Br. J. Cancer"},{"key":"75976_CR28","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-35245-x","volume":"13","author":"S Sivakumar","year":"2022","unstructured":"Sivakumar, S. et al. Tissue and liquid biopsy profiling reveal convergent tumor evolution and therapy evasion in breast cancer. Nat. Commun. 13, 7495 (2022).","journal-title":"Nat. Commun."},{"key":"75976_CR29","doi-asserted-by":"publisher","first-page":"3246","DOI":"10.1200\/JCO.22.00338","volume":"40","author":"F-C Bidard","year":"2022","unstructured":"Bidard, F.-C. 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. 40, 3246\u20133256 (2022).","journal-title":"J. Clin. Oncol."},{"key":"75976_CR30","doi-asserted-by":"publisher","first-page":"1929","DOI":"10.1056\/NEJMoa1813904","volume":"380","author":"F Andr\u00e9","year":"2019","unstructured":"Andr\u00e9, F. et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N. Engl. J. Med. 380, 1929\u20131940 (2019).","journal-title":"N. Engl. J. Med."},{"key":"75976_CR31","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1093\/annonc\/mdz036","volume":"30","author":"R Condorelli","year":"2019","unstructured":"Condorelli, R. et al. Genomic alterations in breast cancer: level of evidence for actionability according to ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Ann. Oncol. 30, 365\u2013373 (2019).","journal-title":"Ann. Oncol."},{"key":"75976_CR32","doi-asserted-by":"crossref","unstructured":"Andre, F. et al. Genomics to select treatment for patients with metastatic breast cancer. Nature 610, 343\u2013348 (2022).","DOI":"10.1038\/s41586-022-05068-3"},{"key":"75976_CR33","first-page":"1005","volume":"40","author":"RH Jones","year":"2022","unstructured":"Jones, R. H. et al. Fulvestrant plus capivasertib versus fulvestrant plus placebo after relapse or progression on an aromatase inhibitor in metastatic, estrogen receptor\u2013positive breast cancer (FAKTION): overall survival and updated progression-free survival data with enhanced biomarker analysis. J. Clin. Orthod. 40, 1005\u20131005 (2022).","journal-title":"J. Clin. Orthod."},{"key":"75976_CR34","unstructured":"Chakravarty, D. et al. OncoKB: a precision oncology knowledge base. JCO Precis. Oncol. 1, 1\u201316 (2017)."},{"key":"75976_CR35","doi-asserted-by":"publisher","first-page":"4274","DOI":"10.1200\/JCO.20.02151","volume":"38","author":"NM Tung","year":"2020","unstructured":"Tung, N. M. et al. TBCRC 048: Phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J. Clin. Oncol. 38, 4274\u20134282 (2020).","journal-title":"J. Clin. Oncol."},{"key":"75976_CR36","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1056\/NEJMoa1706450","volume":"377","author":"M Robson","year":"2017","unstructured":"Robson, M. et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N. Engl. J. Med. 377, 523\u2013533 (2017).","journal-title":"N. Engl. J. Med."},{"key":"75976_CR37","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1056\/NEJMoa1802905","volume":"379","author":"JK Litton","year":"2018","unstructured":"Litton, J. K. et al. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N. Engl. J. Med. 379, 753\u2013763 (2018).","journal-title":"N. Engl. J. Med."},{"key":"75976_CR38","doi-asserted-by":"publisher","first-page":"1925","DOI":"10.1056\/NEJMoa1607303","volume":"375","author":"RS Finn","year":"2016","unstructured":"Finn, R. S. et al. Palbociclib and Letrozole in Advanced Breast Cancer. N. Engl. J. Med. 375, 1925\u20131936 (2016).","journal-title":"N. Engl. J. Med."},{"key":"75976_CR39","doi-asserted-by":"publisher","DOI":"10.1038\/s41523-018-0097-z","volume":"5","author":"S Johnston","year":"2019","unstructured":"Johnston, S. et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer 5, 5 (2019).","journal-title":"NPJ Breast Cancer"},{"key":"75976_CR40","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1056\/NEJMoa1903765","volume":"381","author":"S-A Im","year":"2019","unstructured":"Im, S.-A. et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N. Engl. J. Med. 381, 307\u2013316 (2019).","journal-title":"N. Engl. J. Med."},{"key":"75976_CR41","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1056\/NEJMoa1911149","volume":"382","author":"DJ Slamon","year":"2020","unstructured":"Slamon, D. J. et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N. Engl. J. Med. 382, 514\u2013524 (2020).","journal-title":"N. Engl. J. Med."},{"key":"75976_CR42","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1001\/jamaoncol.2019.4782","volume":"6","author":"GW Sledge Jr.","year":"2020","unstructured":"Sledge, G. W. Jr. et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy-MONARCH 2: a randomized clinical trial. JAMA Oncol. 6, 116\u2013124 (2020).","journal-title":"JAMA Oncol."},{"key":"75976_CR43","doi-asserted-by":"publisher","first-page":"1926","DOI":"10.1056\/NEJMoa1810527","volume":"379","author":"NC Turner","year":"2018","unstructured":"Turner, N. C. et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N. Engl. J. Med. 379, 1926\u20131936 (2018).","journal-title":"N. Engl. J. Med."},{"key":"75976_CR44","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1158\/2159-8290.CD-18-0830","volume":"10","author":"C Costa","year":"2020","unstructured":"Costa, C. et al. PTEN Loss Mediates Clinical Cross-Resistance to CDK4\/6 and PI3K\u03b1 Inhibitors in Breast Cancer. Cancer Discov. 10, 72\u201385 (2020).","journal-title":"Cancer Discov."},{"key":"75976_CR45","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Jim\u00e9nez, F. et al. Pan-cancer whole-genome comparison of primary and metastatic solid tumours. Nature 618, 333\u2013341 (2023).","DOI":"10.1038\/s41586-023-06054-z"},{"key":"75976_CR46","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1038\/ng2006","volume":"39","author":"F Holst","year":"2007","unstructured":"Holst, F. et al. Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer. Nat. Genet. 39, 655\u2013660 (2007).","journal-title":"Nat. Genet."},{"key":"75976_CR47","doi-asserted-by":"publisher","first-page":"1012","DOI":"10.1111\/j.1349-7006.2009.01145.x","volume":"100","author":"S Tomita","year":"2009","unstructured":"Tomita, S. et al. Estrogen receptor alpha gene ESR1 amplification may predict endocrine therapy responsiveness in breast cancer patients. Cancer Sci. 100, 1012\u20131017 (2009).","journal-title":"Cancer Sci."},{"key":"75976_CR48","first-page":"1001","volume":"36","author":"NC Turner","year":"2018","unstructured":"Turner, N. C. et al. Genetic landscape of resistance to CDK4\/6 inhibition in circulating tumor DNA (ctDNA) analysis of the PALOMA3 trial of palbociclib and fulvestrant versus placebo and fulvestrant. J. Clin. Orthod. 36, 1001\u20131001 (2018).","journal-title":"J. Clin. Orthod."},{"key":"75976_CR49","doi-asserted-by":"publisher","first-page":"714","DOI":"10.1126\/science.aaw9032","volume":"366","author":"N Vasan","year":"2019","unstructured":"Vasan, N. et al. Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3K\u03b1 inhibitors. Science 366, 714\u2013723 (2019).","journal-title":"Science"},{"key":"75976_CR50","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1038\/s43018-023-00533-y","volume":"4","author":"I Leshchiner","year":"2023","unstructured":"Leshchiner, I. et al. Inferring early genetic progression in cancers with unobtainable premalignant disease. Nat. Cancer 4, 550\u2013563 (2023).","journal-title":"Nat. Cancer"},{"key":"75976_CR51","doi-asserted-by":"publisher","first-page":"2239","DOI":"10.1016\/j.cell.2021.03.009","volume":"184","author":"SC Dentro","year":"2021","unstructured":"Dentro, S. C. et al. Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes. Cell 184, 2239\u20132254 e2239 (2021).","journal-title":"Cell"},{"key":"75976_CR52","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1101\/gr.139469.112","volume":"23","author":"V Theodorou","year":"2013","unstructured":"Theodorou, V., Stark, R., Menon, S. & Carroll, J. S. GATA3 acts upstream of FOXA1 in mediating ESR1 binding by shaping enhancer accessibility. Genome Res 23, 12\u201322 (2013).","journal-title":"Genome Res"},{"key":"75976_CR53","doi-asserted-by":"publisher","first-page":"2634","DOI":"10.1038\/onc.2009.126","volume":"28","author":"AB Dydensborg","year":"2009","unstructured":"Dydensborg, A. B. et al. GATA3 inhibits breast cancer growth and pulmonary breast cancer metastasis. Oncogene 28, 2634\u20132642 (2009).","journal-title":"Oncogene"},{"key":"75976_CR54","doi-asserted-by":"publisher","first-page":"1329","DOI":"10.1002\/cncr.28566","volume":"120","author":"Y-Z Jiang","year":"2014","unstructured":"Jiang, Y.-Z., Yu, K.-D., Zuo, W.-J., Peng, W.-T. & Shao, Z.-M. GATA3 mutations define a unique subtype of luminal-like breast cancer with improved survival. Cancer 120, 1329\u20131337 (2014).","journal-title":"Cancer"},{"key":"75976_CR55","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1007\/s10549-025-07710-w","volume":"212","author":"AJ Medford","year":"2025","unstructured":"Medford, A. J. et al. Genomic and proteomic profiling of GATA3 mutant metastatic hormone receptor-positive breast cancer and impact on clinical outcomes. Breast Cancer Res. Treat. 212, 437\u2013447 (2025).","journal-title":"Breast Cancer Res. Treat."},{"key":"75976_CR56","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1038\/s41586-022-04975-9","volume":"608","author":"C Herberts","year":"2022","unstructured":"Herberts, C. et al. Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer. Nature 608, 199\u2013208 (2022).","journal-title":"Nature"},{"key":"75976_CR57","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1016\/j.cell.2022.01.003","volume":"185","author":"B Nguyen","year":"2022","unstructured":"Nguyen, B. et al. Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients. Cell 185, 563\u2013575.e511 (2022).","journal-title":"Cell"},{"key":"75976_CR58","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1056\/NEJMoa2501796","volume":"393","author":"KL Jhaveri","year":"2025","unstructured":"Jhaveri, K. L. et al. Overall survival with inavolisib in PIK3CA-mutated advanced breast cancer. N. Engl. J. Med. 393, 151\u2013161 (2025).","journal-title":"N. Engl. J. Med."},{"key":"75976_CR59","doi-asserted-by":"publisher","first-page":"1584","DOI":"10.1056\/NEJMoa2404625","volume":"391","author":"NC Turner","year":"2024","unstructured":"Turner, N. C. et al. Inavolisib-based therapy in PIK3CA-mutated advanced breast cancer. N. Engl. J. Med. 391, 1584\u20131596 (2024).","journal-title":"N. Engl. J. Med."},{"key":"75976_CR60","doi-asserted-by":"publisher","first-page":"3539","DOI":"10.1158\/1078-0432.CCR-17-3831","volume":"24","author":"JI Odegaard","year":"2018","unstructured":"Odegaard, J. I. et al. Validation of a plasma-based comprehensive cancer genotyping assay utilizing orthogonal tissue- and plasma-based methodologies. Clin. Cancer Res. 24, 3539\u20133549 (2018).","journal-title":"Clin. Cancer Res."},{"key":"75976_CR61","doi-asserted-by":"crossref","unstructured":"Campone, M. et al. Abstract OT2-11-03: AMEERA-1: Phase 1\/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with alpelisib in postmenopausal women with ER+\/human epidermal growth factor receptor 2-negative (HER2-)PIK3CA-mutated advanced breast cancer. Cancer Res. 82, OT2-11-03-OT12-11-03 (2022).","DOI":"10.1158\/1538-7445.SABCS21-OT2-11-03"},{"key":"75976_CR62","unstructured":"Rugo, H. S. et al. ELEVATE: a phase 1b\/2, open-label, umbrella study evaluating elacestrant in various combinations in."},{"key":"75976_CR63","first-page":"1032","volume":"40","author":"M Oliveira","year":"2022","unstructured":"Oliveira, M. et al. Serena-1: Updated analyses from a phase 1 study (parts C\/D) of the next-generation oral SERD camizestrant (AZD9833) in combination with palbociclib, in women with ER-positive, HER2-negative advanced breast cancer. J. Clin. Orthod. 40, 1032\u20131032 (2022).","journal-title":"J. Clin. Orthod."},{"key":"75976_CR64","first-page":"LBA1004","volume":"40","author":"K Kalinsky","year":"2022","unstructured":"Kalinsky, K. et al. A randomized, phase II trial of fulvestrant or exemestane with or without ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4\/6 inhibition (CDK 4\/6i) in patients (pts) with unresectable or hormone receptor\u2013positive (HR+), HER2-negative metastatic breast cancer (MBC): MAINTAIN trial. J. Clin. Orthod. 40, LBA1004\u2013LBA1004 (2022).","journal-title":"J. Clin. Orthod."},{"key":"75976_CR65","doi-asserted-by":"crossref","unstructured":"Wander, S. A. et al. Clinical outcomes with abemaciclib after prior CDK4\/6 inhibitor progression in breast cancer: a multicenter experience. J. Natl. Compr. Canc. Netw. 19, 1\u20138 (2021).","DOI":"10.6004\/jnccn.2020.7662"},{"key":"75976_CR66","first-page":"TPS1104","volume":"36","author":"EL Mayer","year":"2018","unstructured":"Mayer, E. L. et al. Palbociclib after CDK and endocrine therapy (PACE): a randomized phase II study of fulvestrant, palbociclib, and avelumab for endocrine pre-treated ER+\/HER2- metastatic breast cancer. J. Clin. Orthod. 36, TPS1104\u2013TPS1104 (2018).","journal-title":"J. Clin. Orthod."},{"key":"75976_CR67","unstructured":"Bidard, F.-C. et al. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 23, 1367\u20131377 (2022)."},{"key":"75976_CR68","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1001\/jamaoncol.2020.5161","volume":"7","author":"K Jensen","year":"2021","unstructured":"Jensen, K. et al. Association of clonal hematopoiesis in DNA repair genes with prostate cancer plasma cell-free DNA testing interference. JAMA Oncol. 7, 107\u2013110 (2021.","journal-title":"JAMA Oncol."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-75976-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-75976-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-75976-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T11:04:10Z","timestamp":1792667050000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-75976-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,22]]},"references-count":68,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["75976"],"URL":"https:\/\/doi.org\/10.1038\/s41467-026-75976-9","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,22]]},"assertion":[{"value":"9 February 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 September 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A.J.M. has served as an advisor\/consultant for AstraZeneca, Asuragen, Edgewood Oncology, Guardant Health, Illumina, Myriad Genetics, Natera, Novartis, Neogenomics, Precede Biosciences, SAGA Diagnostics, Reversing Early Recurrence, and Science for America, outside the submitted work. Grant statement: G.G. is an inventor on patent applications filed by the Broad Institute including those\u00a0related to MSMuTect, MSMutSig, POLYSOLVER, SignatureAnalyzer-GPU, MSEye, MinumuMM-seq, DLBclass, HapASeg, Tonly2, MSIDetect, TuFEst and ABSOLUTE2. A full list of Dr. Getz\u2019s publicly available patent applications can be requested from the Broad\u2019s legal team at patents@broadinstitute.org. G.G. receives research funds from IBM, Pharmacyclics\/Abbvie, Bayer, Genentech, Calico, Ultima Genomics,\u00a0Inocras, Google, Kite, AstraZeneca and Novartis and is a founder of and a consultant to and holds privately held equity in Scorpion Therapeutics; he is also a founder of and holds privately held equity in PreDICTA Biosciences; and he is\u00a0consultant\u00a0and\u00a0holds privately held equity in Antares Therapeutics. I.L. is a consultant for PACT Pharma and is co-founder, scientific advisor and holds privately in NoRD Bio. I.L. receives research funding or support from AstraZeneca, Ultima Genomics and BeOne Medicines. L.A.K. is a former employee of Guardant Health. L.M.S. is a consultant or on advisory board for Novartis, Daiichi Pharma, Astra Zeneca, Eli Lilly, Precede, Seagen, Pfizer; Institutional research support: Merck, Genentech, Gilead, Eli Lilly, Astra Zeneca. Beverly Moy and an immediate family member who consulted for Guardant Health in 2024. S.W. is a consultant or on advisory board for Foundation Medicine, Veracyte, Hologic, Eli Lilly, Biovica, Pfizer\/Arvinas, Puma Biotechnology, Novartis, AstraZeneca, Genentech, Regor Therapeutics, Stemline\/Menarini, Gilead; Education\/Speaking: Eli Lilly, Guardant Health, 2ndMD and receives institutional research support from Genentech, Eli Lilly, Pfizer\/Arvinas, Nuvation Bio, Regor Therapeutics, Sermonix, Puma Biotechnology, Stemline\/Menarini, Phoenix Molecular Designs. N.V. receives institutional research funding from: Merck, Daewha, Radius, Novartis, Pfizer, Stemline, Theradex and on advisory board of AbbVie, OncoSec, Gilead, Aadi, TerSera, Novartis, Daiichi, Pfizer, IDEOlogy Health. S.J.I. is a consultant for Veracyte, Aktis; Institutional Research: Genentech, Agendia, AstraZeneca, Merck. D.J. is a consultant for Amgen, AstraZeneca, Blueprint Medicines Corporation, EISAI Inc, Eli Lilly and Company, F. Hoffman-La Roche, Genentech, Infinity Pharmaceuticals, Mapkure, Novartis, Pfizer, Relay Therapeutics, Ribbon Therapeutics, Scorpion Therapeutics, Seagen Inc, Syros Pharmaceuticals, Takeda Oncology, Vibliome. A.A.D. participated in scientific advisory boards with Biotheranostics, NeoGenomics Laboratories, and Pfizer; receives grant support from the Breast Cancer Alliance; and has received travel support from DAVA Oncology. L.G. is a consultant or on advisory board for AstraZeneca, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Incyte, Novartis, Pfizer, Merck Sharp & Dohme, Menarini Stemline, Abbvie, Gilead; Research Funding: Gilead; Travel Expenses: Menarini Stemline, Novartis, Gilead, Pfizer. A.S. is on advisory board for Novartis, Lily, AstraZeneca, Daiichi Sankyo, and speaker\u2019s bureau for Gilead and AstraZeneca. B.H.P. receives royalties from Horizon Discovery, LTD; is on advisory board for Celcuity, Inc.; receives research funds from Guardant Health, Tempus, Personalis and is a non-paid consultant and collaborator with Tempus; consultant Casdin Capital and Astrin Biosciences. Ad.B. is a consultant for AstraZeneca, Pfizer, Novartis, Lilly, Genentech\/Roche, Daiichi Sankyo, Merck, Agendia, Sanofi, Puma, Myriad, Gilead, Bria Cell and receives research support from Agendia and Astrazeneca. J.O. is a consultant for AADI Bioscience, Agendia, Amgen Biotechnology, Aptitude Health, AstraZeneca, BioNTech, Bristol Myers Squibb, Daiichi Sankyo, Duality, Eisai, Eli Lilly, Exact Sciences, Ellipses, G1 Therapeutics, Genentech, Gilead Sciences, Guardant Health, Hibercell, Jazz Pharmaceuticals, J&J, Menarini-Stemline, Merck, Mersana, Natera, Novartis, Pfizer, Pierre Fabre Pharmaceuticals. B.N. is an employee for Guardant Health. L.E. is a consultant for Gilead, AstraZeneca, Kisoji Atavistik and receives research funding from Sanofi and Eisai. M.C. is a consultant or on advisory board for AstraZeneca\/Daiichi Sankyo, BriaCell, Datar Genomics, Menarini Silicon Biosystems, Merck, Olaris, Pfizer, Repare Therapeutics, Celcuity, Lilly, Sermonix Pharmaceuticals, and Syantra and uncompensated member of Precision Medicine Action for Cancer (PMAC) Board of Directors. A.B. receives personal fees from Novartis, Genentech, Pfizer, Merck, Novartis, Genentech\/Roche, Radius, Innocrin, Sanofi, AstraZeneca\/Daiichi Sankyo, Lilly, Gilead Sciences, Menarini, and Mersana and research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics, and AstraZeneca\/Daiichi Sankyo. L.G. is a consultant or on advisory board for AstraZeneca, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Incyte, Novartis, Pfizer, Merck Sharp & Dohme, Menarini Stemline, Abbvie, Gilead; receives research funding from Gilead and travel expenses from Menarini Stemline, Novartis, Gilead, Pfizer. The other authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"11023"}}