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dc.contributor.authorSmyth, ECen_US
dc.contributor.authorCafferkey, Cen_US
dc.contributor.authorLoehr, Aen_US
dc.contributor.authorWaddell, Ten_US
dc.contributor.authorBegum, Ren_US
dc.contributor.authorPeckitt, Cen_US
dc.contributor.authorHarding, TCen_US
dc.contributor.authorNguyen, Men_US
dc.contributor.authorOkines, AFen_US
dc.contributor.authorRaponi, Men_US
dc.contributor.authorRao, Sen_US
dc.contributor.authorWatkins, Den_US
dc.contributor.authorStarling, Nen_US
dc.contributor.authorMiddleton, GWen_US
dc.contributor.authorWadsley, Jen_US
dc.contributor.authorMansoor, Wen_US
dc.contributor.authorCrosby, Ten_US
dc.contributor.authorWotherspoon, Aen_US
dc.contributor.authorChau, Ien_US
dc.contributor.authorCunningham, Den_US
dc.coverage.spatialUnited Statesen_US
dc.date.accessioned2019-02-20T08:22:03Z
dc.date.issued2018-11-30en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/30613349en_US
dc.identifier26336en_US
dc.identifier.citationOncotarget, 2018, 9 (94), pp. 36654 - 36665en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3074
dc.identifier.eissn1949-2553en_US
dc.identifier.doi10.18632/oncotarget.26336en_US
dc.description.abstractBackground: Homologous recombination deficiency (HRD) measured using a genomic signature for loss of heterozygosity (LOH) predicts benefit from rucaparib in ovarian cancer. We hypothesized that some oesophagogastric cancers will have high-LOH which would be prognostic in patients treated with platinum chemotherapy. Methods: Diagnostic biopsy DNA from patients treated in the REAL3 trial was sequenced using the Foundation Medicine T5 next-generation sequencing (NGS) assay. An algorithm quantified the percentage of interrogable genome with LOH. Multidimensional optimization was performed to identify a cut-off dichotomizing the population into LOH-high and low groups associated with differential survival outcomes. Results: Of 158 available samples, 117 were successfully sequenced; LOH was derived for 74 of these. A cut-off of 21% genomic LOH defined an LOH-high subgroup (n=10, 14% of population) who had median overall survival (OS) of 18.3 months (m) versus 11m for the LOH-low group (HR 0.55 95% CI 0.19-0.97, p= 0.10). Progression free survival (PFS) for LOH-high and LOH-low groups was 10.7m and 7.3m (HR 0.61 (95% CI 0.21 - 1.09, p=0.09). Sensitivity analysis censoring operated patients (n=4), demonstrated OS of 18.3m vs. 10.2m (HR 0.43, 95% CI (0.20-0.92), p=0.02; PFS was 10.5m vs. 7.2m (HR 0.55, (95% CI 0.26-1.17), p=0.09 for LOH-high and LOH-low. Conclusion: HRD assessment using an algorithmically derived LOH signature on a standard NGS panel identifies oesophagogastric cancer patients with high LOH who have prolonged survival when treated with platinum chemotherapy. Validation work will determine the signature's predictive value in patients treated with a PARP inhibitor and with platinum chemotherapy.en_US
dc.format.extent36654 - 36665en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectchemotherapyen_US
dc.subjectgastric canceren_US
dc.subjecthomologous recombination deficiencyen_US
dc.subjectloss of heterozygosityen_US
dc.subjectoesophageal canceren_US
dc.titleGenomic loss of heterozygosity and survival in the REAL3 trial.en_US
dc.typeJournal Article
dcterms.dateAccepted2018-10-06en_US
rioxxterms.versionofrecord10.18632/oncotarget.26336en_US
rioxxterms.licenseref.startdate2018-11-30en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfOncotargeten_US
pubs.issue94en_US
pubs.notesNot knownen_US
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/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/Royal Marsden Clinical Units
pubs.publication-statusPublished onlineen_US
pubs.volume9en_US
pubs.embargo.termsNot knownen_US
icr.researchteamGastrointestinal Cancers Clinical Trialsen_US
icr.researchteamMedicine (RMH Smith Cunningham)en_US
dc.contributor.icrauthorCunningham, Daviden_US
dc.contributor.icrauthorStarling, Naureenen_US
dc.contributor.icrauthorChau, Ianen_US


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