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dc.contributor.authorKhan, KH
dc.contributor.authorCunningham, D
dc.contributor.authorWerner, B
dc.contributor.authorVlachogiannis, G
dc.contributor.authorSpiteri, I
dc.contributor.authorHeide, T
dc.contributor.authorMateos, JF
dc.contributor.authorVatsiou, A
dc.contributor.authorLampis, A
dc.contributor.authorDamavandi, MD
dc.contributor.authorLote, H
dc.contributor.authorHuntingford, IS
dc.contributor.authorHedayat, S
dc.contributor.authorChau, I
dc.contributor.authorTunariu, N
dc.contributor.authorMentrasti, G
dc.contributor.authorTrevisani, F
dc.contributor.authorRao, S
dc.contributor.authorAnandappa, G
dc.contributor.authorWatkins, D
dc.contributor.authorStarling, N
dc.contributor.authorThomas, J
dc.contributor.authorPeckitt, C
dc.contributor.authorKhan, N
dc.contributor.authorRugge, M
dc.contributor.authorBegum, R
dc.contributor.authorHezelova, B
dc.contributor.authorBryant, A
dc.contributor.authorJones, T
dc.contributor.authorProszek, P
dc.contributor.authorFassan, M
dc.contributor.authorHahne, JC
dc.contributor.authorHubank, M
dc.contributor.authorBraconi, C
dc.contributor.authorSottoriva, A
dc.contributor.authorValeri, N
dc.date.accessioned2018-08-23T10:37:24Z
dc.date.issued2018-10
dc.identifier.citationCancer discovery, 2018, 8 (10), pp. 1270 - 1285
dc.identifier.issn2159-8274
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2373
dc.identifier.eissn2159-8290
dc.identifier.doi10.1158/2159-8290.cd-17-0891
dc.description.abstractSequential profiling of plasma cell-free DNA (cfDNA) holds immense promise for early detection of patient progression. However, how to exploit the predictive power of cfDNA as a liquid biopsy in the clinic remains unclear. RAS pathway aberrations can be tracked in cfDNA to monitor resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer. In this prospective phase II clinical trial of single-agent cetuximab in RAS wild-type patients, we combine genomic profiling of serial cfDNA and matched sequential tissue biopsies with imaging and mathematical modeling of cancer evolution. We show that a significant proportion of patients defined as RAS wild-type based on diagnostic tissue analysis harbor aberrations in the RAS pathway in pretreatment cfDNA and, in fact, do not benefit from EGFR inhibition. We demonstrate that primary and acquired resistance to cetuximab are often of polyclonal nature, and these dynamics can be observed in tissue and plasma. Furthermore, evolutionary modeling combined with frequent serial sampling of cfDNA allows prediction of the expected time to treatment failure in individual patients. This study demonstrates how integrating frequently sampled longitudinal liquid biopsies with a mathematical framework of tumor evolution allows individualized quantitative forecasting of progression, providing novel opportunities for adaptive personalized therapies. Significance: Liquid biopsies capture spatial and temporal heterogeneity underpinning resistance to anti-EGFR monoclonal antibodies in colorectal cancer. Dense serial sampling is needed to predict the time to treatment failure and generate a window of opportunity for intervention. Cancer Discov; 8(10); 1270-85. ©2018 AACR. See related commentary by Siravegna and Corcoran, p. 1213 This article is highlighted in the In This Issue feature, p. 1195 .
dc.formatPrint-Electronic
dc.format.extent1270 - 1285
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectHumans
dc.subjectColorectal Neoplasms
dc.subjectTreatment Failure
dc.subjectModels, Theoretical
dc.subjectAdult
dc.subjectAged
dc.subjectAged, 80 and over
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectClinical Trials as Topic
dc.subjectClonal Evolution
dc.subjectTime-to-Treatment
dc.subjectLiquid Biopsy
dc.titleLongitudinal Liquid Biopsy and Mathematical Modeling of Clonal Evolution Forecast Time to Treatment Failure in the PROSPECT-C Phase II Colorectal Cancer Clinical Trial.
dc.typeJournal Article
dcterms.dateAccepted2018-07-05
rioxxterms.versionofrecord10.1158/2159-8290.cd-17-0891
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-10
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancer discovery
pubs.issue10
pubs.notes12 months
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/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials/Gastrointestinal Cancers Clinical Trials (hon.)
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/ICR Divisions/Molecular Pathology/Translational Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Genomics/Translational Genomics (hon.)
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/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials/Gastrointestinal Cancers Clinical Trials (hon.)
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/ICR Divisions/Molecular Pathology/Translational Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Genomics/Translational Genomics (hon.)
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.volume8
pubs.embargo.terms12 months
icr.researchteamSignal Transduction & Molecular Pharmacologyen_US
icr.researchteamGastrointestinal Cancers Clinical Trialsen_US
icr.researchteamMedicine (RMH Smith Cunningham)en_US
icr.researchteamEvolutionary Genomics & Modellingen_US
icr.researchteamFunctional Genomicsen_US
icr.researchteamGastrointestinal Cancer Biology and Genomicsen_US
icr.researchteamTranslational Genomicsen_US
dc.contributor.icrauthorSpiteri Sagastume, Mariaen
dc.contributor.icrauthorHeide, Timonen
dc.contributor.icrauthorBraconi, Chiaraen
dc.contributor.icrauthorHahne, Jensen
dc.contributor.icrauthorDarvish Damavandi, Mahnazen
dc.contributor.icrauthorLote, Hazelen
dc.contributor.icrauthorLampis, Andreaen
dc.contributor.icrauthorHedayat-Husseyin, Somaiehen
dc.contributor.icrauthorFernandez Mateos, Javieren
dc.contributor.icrauthorAnandappa, Gayathrien
dc.contributor.icrauthorSottoriva, Andreaen
dc.contributor.icrauthorCunningham, Daviden
dc.contributor.icrauthorChau, Ianen
dc.contributor.icrauthorStarling, Naureenen
dc.contributor.icrauthorValeri, Nicolaen
dc.contributor.icrauthorHubank, Michaelen
dc.contributor.icrauthorTunariu, Ninaen


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