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dc.contributor.authorPaoletti, Costanza
dc.contributor.authorSchiavon, Gaia
dc.contributor.authorDolce, Emily M
dc.contributor.authorDarga, Elizabeth P
dc.contributor.authorCarr, T Hedley
dc.contributor.authorGeradts, Joseph
dc.contributor.authorHoch, Matthias
dc.contributor.authorKlinowska, Teresa
dc.contributor.authorLindemann, Justin
dc.contributor.authorMarshall, Gayle
dc.contributor.authorMorgan, Shethah
dc.contributor.authorPatel, Parul
dc.contributor.authorRowlands, Vicky
dc.contributor.authorSathiyayogan, Nitharsan
dc.contributor.authorAung, Kimberly
dc.contributor.authorHamilton, Erika
dc.contributor.authorPatel, Manish
dc.contributor.authorArmstrong, Anne
dc.contributor.authorJhaveri, Komal
dc.contributor.authorIm, Seock-Ah
dc.contributor.authorIqbal, Nadia
dc.contributor.authorButt, Fouziah
dc.contributor.authorDive, Caroline
dc.contributor.authorHarrington, Elizabeth A
dc.contributor.authorBarrett, J Carl
dc.contributor.authorBaird, Richard
dc.contributor.authorHayes, Daniel F
dc.date.accessioned2018-11-17T00:31:51Z
dc.date.available2018-11-17T00:31:51Z
dc.date.issued2018-12-01
dc.identifier.issn1078-0432
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285383
dc.description.abstractPURPOSE: Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER)-positive metastatic breast cancers include, among others, ER loss and acquired activating mutations in the ligand-binding domain of the ER gene (ESR1LBDm). ESR1 mutational mediated resistance may be overcome by selective ER degraders (SERD). During the first-in-human study of oral SERD AZD9496, early changes in circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) were explored as potential noninvasive tools, alongside paired tumor biopsies, to assess pharmacodynamics and early efficacy. EXPERIMENTAL DESIGN: CTC were enumerated/phenotyped for ER and Ki67 using CellSearch in serial blood draws. ctDNA was assessed for the most common ESR1LBDm by droplet digital PCR (BioRad). RESULTS: Before starting AZD9496, 11 of 43 (25%) patients had ≥5 CTC/7.5 mL whole blood (WB), none of whom underwent reduction to <5 CTC/7.5 mL WB on C1D15. Five of 11 patients had baseline CTC-ER+, two of whom had CTC-ER+ reduction. CTC-Ki67 status did not change appreciably. Patients with ≥5 CTC/7.5 mL WB before treatment had worse progression-free survival (PFS) than patients with <5 CTC (P = 0.0003). Fourteen of 45 (31%) patients had ESR1LBDm + ctDNA at baseline, five of whom had ≥2 unique mutations. Baseline ESR1LBDm status was not prognostic. Patients with persistently elevated CTC and/or ESR1LBDm + ctDNA at C1D15 had worse PFS than patients who did not (P = 0.0007). CONCLUSIONS: Elevated CTC at baseline was a strong prognostic factor in this cohort. Early on-treatment changes were observed in CTC-ER+ and ESR1LBDm + ctDNA, but not in overall CTC number. Integrating multiple biomarkers in prospective trials may improve outcome prediction and ET resistance mechanisms' identification over a single biomarker.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherAmerican Association for Cancer Research (AACR)
dc.subjectHumans
dc.subjectBreast Neoplasms
dc.subjectNeoplasm Metastasis
dc.subjectEstrogen Antagonists
dc.subjectEstrogen Receptor alpha
dc.subjectAntineoplastic Agents, Hormonal
dc.subjectNeoplasm Staging
dc.subjectPrognosis
dc.subjectImmunohistochemistry
dc.subjectDrug Resistance, Neoplasm
dc.subjectMutation
dc.subjectFemale
dc.subjectKaplan-Meier Estimate
dc.subjectBiomarkers, Tumor
dc.subjectLiquid Biopsy
dc.subjectCirculating Tumor DNA
dc.titleCirculating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial.
dc.typeArticle
prism.endingPage5872
prism.issueIdentifier23
prism.publicationDate2018
prism.publicationNameClin Cancer Res
prism.startingPage5860
prism.volume24
dc.identifier.doi10.17863/CAM.32749
dcterms.dateAccepted2018-07-31
rioxxterms.versionofrecord10.1158/1078-0432.CCR-18-1569
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-12
dc.contributor.orcidBaird, Richard [0000-0001-7071-6483]
dc.identifier.eissn1557-3265
rioxxterms.typeJournal Article/Review
cam.issuedOnline2018-08-06
rioxxterms.freetoread.startdate2019-08-06


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