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dc.contributor.authorSmyth, EC
dc.contributor.authorVlachogiannis, G
dc.contributor.authorHedayat, S
dc.contributor.authorHarbery, A
dc.contributor.authorHulkki-Wilson, S
dc.contributor.authorSalati, M
dc.contributor.authorKouvelakis, K
dc.contributor.authorFernandez-Mateos, J
dc.contributor.authorCresswell, GD
dc.contributor.authorFontana, E
dc.contributor.authorSeidlitz, T
dc.contributor.authorPeckitt, C
dc.contributor.authorHahne, JC
dc.contributor.authorLampis, A
dc.contributor.authorBegum, R
dc.contributor.authorWatkins, D
dc.contributor.authorRao, S
dc.contributor.authorStarling, N
dc.contributor.authorWaddell, T
dc.contributor.authorOkines, A
dc.contributor.authorCrosby, T
dc.contributor.authorMansoor, W
dc.contributor.authorWadsley, J
dc.contributor.authorMiddleton, G
dc.contributor.authorFassan, M
dc.contributor.authorWotherspoon, A
dc.contributor.authorBraconi, C
dc.contributor.authorChau, I
dc.contributor.authorVivanco, I
dc.contributor.authorSottoriva, A
dc.contributor.authorStange, DE
dc.contributor.authorCunningham, D
dc.contributor.authorValeri, N
dc.date.accessioned2020-11-24T12:00:50Z
dc.date.issued2020-11-16
dc.identifier.citationGut, 2020
dc.identifier.issn0017-5749
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4242
dc.identifier.eissn1468-3288
dc.identifier.doi10.1136/gutjnl-2020-322658
dc.description.abstractObjective Epidermal growth factor receptor (EGFR) inhibition may be effective in biomarker-selected populations of advanced gastro-oesophageal adenocarcinoma (aGEA) patients. Here, we tested the association between outcome and EGFR copy number (CN) in pretreatment tissue and plasma cell-free DNA (cfDNA) of patients enrolled in a randomised first-line phase III clinical trial of chemotherapy or chemotherapy plus the anti-EGFR monoclonal antibody panitumumab in aGEA (NCT00824785).Design EGFR CN by either fluorescence in situ hybridisation (n=114) or digital-droplet PCR in tissues (n=250) and plasma cfDNAs (n=354) was available for 474 (86%) patients in the intention-to-treat (ITT) population. Tissue and plasma low-pass whole-genome sequencing was used to screen for coamplifications in receptor tyrosine kinases. Interaction between chemotherapy and EGFR inhibitors was modelled in patient-derived organoids (PDOs) from aGEA patients.Results EGFR amplification in cfDNA correlated with poor survival in the ITT population and similar trends were observed when the analysis was conducted in tissue and plasma by treatment arm. EGFR inhibition in combination with chemotherapy did not correlate with improved survival, even in patients with significant EGFR CN gains. Addition of anti-EGFR inhibitors to the chemotherapy agent epirubicin in PDOs, resulted in a paradoxical increase in viability and accelerated progression through the cell cycle, associated with p21 and cyclin B1 downregulation and cyclin E1 upregulation, selectively in organoids from EGFR -amplified aGEA.Conclusion EGFR CN can be accurately measured in tissue and liquid biopsies and may be used for the selection of aGEA patients. EGFR inhibitors may antagonise the antitumour effect of anthracyclines with important implications for the design of future combinatorial trials.
dc.formatPrint-Electronic
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleEGFR amplification and outcome in a randomised phase III trial of chemotherapy alone or chemotherapy plus panitumumab for advanced gastro-oesophageal cancers.
dc.typeJournal Article
dcterms.dateAccepted2020-10-15
rioxxterms.versionofrecord10.1136/gutjnl-2020-322658
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2020-11-16
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfGut
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Evolutionary Genomics & Modelling
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gastrointestinal Cancer Biology and Genomics
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/16/17 Starting Cohort
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Evolutionary Genomics & Modelling
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gastrointestinal Cancer Biology and Genomics
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/16/17 Starting Cohort
pubs.publication-statusPublished
pubs.embargo.termsNot known
icr.researchteamMedicine (RMH Smith Cunningham)en_US
icr.researchteamEvolutionary Genomics & Modellingen_US
icr.researchteamFunctional Genomicsen_US
icr.researchteamGastrointestinal Cancer Biology and Genomicsen_US
dc.contributor.icrauthorHedayat-Husseyin, Somaiehen
dc.contributor.icrauthorHahne, Jensen
dc.contributor.icrauthorLampis, Andreaen
dc.contributor.icrauthorCunningham, Daviden
dc.contributor.icrauthorChau, Ianen
dc.contributor.icrauthorValeri, Nicolaen
dc.contributor.icrauthorSottoriva, Andreaen


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