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Timely monitoring of the molecular events associated with response\/progression by serial tissue biopsies is logistically difficult. Use of liquid biopsies, including circulating tumor cells (CTC) and circulating tumor DNA (ctDNA), might provide highly informative, yet easily obtainable, evidence for better precision oncology care. Although ctDNA profiling has been well investigated, the CTC precision oncology genomic landscape and the advantages it may offer over ctDNA in ER\u2010POS breast cancer remain largely unexplored. Whole\u2010blood (WB) specimens were collected at serial time points from patients with advanced ER\u2010POS\/HER2\u2010negative (NEG) advanced breast cancer in a phase I trial of AZD9496, an oral selective ER degrader (SERD) ET. Individual CTC were isolated from WB using tandem CellSearch\n \u00ae<\/jats:sup>\n \/DEPArray\u2122 technologies and genomically profiled by targeted single\u2010cell DNA next\u2010generation sequencing (scNGS). High\u2010quality CTC (\n n<\/jats:italic>\n \u2009=\u2009123) from 12 patients profiled by scNGS showed 100% concordance with ctDNA detection of driver estrogen receptor \u03b1 (\n ESR1<\/jats:italic>\n ) mutations. We developed a novel CTC\u2010based framework for precision medicine actionability reporting (MI\u2010CTCseq) that incorporates novel features, such as clonal predominance and zygosity of targetable alterations, both unambiguously identifiable in CTC compared to ctDNA. Thus, we nominated opportunities for targeted therapies in 73% of patients, directed at alterations in phosphatidylinositol\u20104,5\u2010bisphosphate 3\u2010kinase catalytic subunit alpha (\n PIK3CA<\/jats:italic>\n ), fibroblast growth factor receptor 2 (\n FGFR2<\/jats:italic>\n ), and KIT proto\u2010oncogene, receptor tyrosine kinase (\n KIT<\/jats:italic>\n ). Intrapatient, inter\u2010CTC genomic heterogeneity was observed, at times between time points, in subclonal alterations. Our analysis suggests that serial monitoring of the CTC genome is feasible and should enable real\u2010time tracking of tumor evolution during progression, permitting more combination precision medicine interventions.\n <\/jats:p>","DOI":"10.1002\/1878-0261.13150","type":"journal-article","created":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T03:26:56Z","timestamp":1638761216000},"page":"1969-1985","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Serial monitoring of genomic alterations in circulating tumor cells of ER\u2010positive\/HER2\u2010negative advanced breast cancer: feasibility of precision oncology biomarker detection"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4691-656X","authenticated-orcid":false,"given":"Andi K.","family":"Cani","sequence":"first","affiliation":[{"name":"Division of Hematology and Oncology Department of Internal Medicine University of Michigan Medical School Ann Arbor MI USA"},{"name":"Rogel Cancer Center Michigan Medicine University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily M.","family":"Dolce","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology Department of Internal Medicine University of Michigan Medical School Ann Arbor MI USA"},{"name":"Rogel Cancer Center Michigan Medicine University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7728-9162","authenticated-orcid":false,"given":"Elizabeth P.","family":"Darga","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology Department of Internal Medicine University of Michigan Medical School Ann Arbor MI USA"},{"name":"Rogel Cancer Center Michigan Medicine University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pathology Michigan Medicine University of Michigan Ann Arbor MI USA"},{"name":"Michigan Center for Translational Pathology Michigan Medicine University of Michigan Ann Arbor MI USA"},{"name":"Department of Computational Medicine and Bioinformatics University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia\u2010Jen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology Michigan Medicine University of Michigan Ann Arbor MI USA"},{"name":"Michigan Center for Translational Pathology Michigan Medicine University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jackie","family":"Pierce","sequence":"additional","affiliation":[{"name":"Cancer Research UK Manchester Institute Cancer Biomarker Centre University of Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kieran","family":"Bradbury","sequence":"additional","affiliation":[{"name":"Cancer Research UK Manchester Institute Cancer Biomarker Centre University of Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Kilgour","sequence":"additional","affiliation":[{"name":"Cancer Research UK Manchester Institute Cancer Biomarker Centre University of Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Aung","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology Department of Internal Medicine University of Michigan Medical School Ann Arbor MI USA"},{"name":"Rogel Cancer Center Michigan Medicine University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaia","family":"Schiavon","sequence":"additional","affiliation":[{"name":"Research and Early Development Oncology R&D AstraZeneca Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Carroll","sequence":"additional","affiliation":[{"name":"Research and Early Development Oncology R&D AstraZeneca Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. 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