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dc.contributor.authorCani, Andi K
dc.contributor.authorDolce, Emily M
dc.contributor.authorDarga, Elizabeth P
dc.contributor.authorHu, Kevin
dc.contributor.authorLiu, Chia-Jen
dc.contributor.authorPierce, Jackie
dc.contributor.authorBradbury, Kieran
dc.contributor.authorKilgour, Elaine
dc.contributor.authorAung, Kimberly
dc.contributor.authorSchiavon, Gaia
dc.contributor.authorCarroll, Danielle
dc.contributor.authorCarr, T Hedley
dc.contributor.authorKlinowska, Teresa
dc.contributor.authorLindemann, Justin
dc.contributor.authorMarshall, Gayle
dc.contributor.authorRowlands, Vicky
dc.contributor.authorHarrington, Elizabeth A
dc.contributor.authorBarrett, J Carl
dc.contributor.authorSathiyayogan, Nitharsan
dc.contributor.authorMorrow, Christopher
dc.contributor.authorSero, Valeria
dc.contributor.authorArmstrong, Anne C
dc.contributor.authorBaird, Richard
dc.contributor.authorHamilton, Erika
dc.contributor.authorIm, Seock-Ah
dc.contributor.authorJhaveri, Komal
dc.contributor.authorPatel, Manish R
dc.contributor.authorDive, Caroline
dc.contributor.authorTomlins, Scott A
dc.contributor.authorUdager, Aaron M
dc.contributor.authorHayes, Daniel F
dc.contributor.authorPaoletti, Costanza
dc.date.accessioned2021-12-24T00:31:23Z
dc.date.available2021-12-24T00:31:23Z
dc.date.issued2022-05
dc.identifier.issn1574-7891
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/331769
dc.description.abstractNearly all estrogen receptor (ER)-positive (POS) metastatic breast cancers become refractory to endocrine (ET) and other therapies, leading to lethal disease presumably due to evolving genomic alterations. 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-POS breast cancer remain largely unexplored. Whole-blood (WB) specimens were collected at serial time points from patients with advanced ER-POS/HER2-negative (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® /DEPArray™ technologies and genomically profiled by targeted single-cell DNA next-generation sequencing (scNGS). High-quality CTC (n = 123) from 12 patients profiled by scNGS showed 100% concordance with ctDNA detection of driver estrogen receptor α (ESR1) mutations. We developed a novel CTC-based framework for precision medicine actionability reporting (MI-CTCseq) 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-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), fibroblast growth factor receptor 2 (FGFR2), and KIT proto-oncogene, receptor tyrosine kinase (KIT). Intrapatient, inter-CTC 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-time tracking of tumor evolution during progression, permitting more combination precision medicine interventions.
dc.format.mediumPrint-Electronic
dc.publisherWiley
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectLiquid biopsy
dc.subjectcirculating tumor DNA
dc.subjectcirculating tumor cells
dc.subjectprecision medicine
dc.subjecttumor evolution
dc.subjecttumor heterogeneity
dc.titleSerial monitoring of genomic alterations in circulating tumor cells of ER-positive/HER2-negative advanced breast cancer: feasibility of precision oncology biomarker detection.
dc.typeArticle
dc.publisher.departmentDepartment of Oncology
dc.date.updated2021-12-22T13:14:56Z
prism.publicationDate2021
prism.publicationNameMol Oncol
dc.identifier.doi10.17863/CAM.79218
dcterms.dateAccepted2021-12-01
rioxxterms.versionofrecord10.1002/1878-0261.13150
rioxxterms.versionVoR
dc.contributor.orcidCani, Andi K [0000-0003-4691-656X]
dc.contributor.orcidDarga, Elizabeth P [0000-0001-7728-9162]
dc.contributor.orcidMorrow, Christopher [0000-0003-1524-9426]
dc.contributor.orcidBaird, Richard [0000-0001-7071-6483]
dc.identifier.eissn1878-0261
rioxxterms.typeJournal Article/Review
cam.issuedOnline2021-12-20
cam.depositDate2021-12-22
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International