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dc.contributor.authorSipos, O
dc.contributor.authorTovey, H
dc.contributor.authorQuist, J
dc.contributor.authorHaider, S
dc.contributor.authorNowinski, S
dc.contributor.authorGazinska, P
dc.contributor.authorKernaghan, S
dc.contributor.authorToms, C
dc.contributor.authorMaguire, S
dc.contributor.authorOrr, N
dc.contributor.authorLinn, SC
dc.contributor.authorOwen, J
dc.contributor.authorGillett, C
dc.contributor.authorPinder, SE
dc.contributor.authorBliss, JM
dc.contributor.authorTutt, A
dc.contributor.authorCheang, MCU
dc.contributor.authorGrigoriadis, A
dc.date.accessioned2020-11-27T15:48:10Z
dc.date.issued2021-01
dc.identifier.citationAnnals of oncology : official journal of the European Society for Medical Oncology, 2021, 32 (1), pp. 58 - 65
dc.identifier.issn0923-7534
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4243
dc.identifier.eissn1569-8041
dc.identifier.doi10.1016/j.annonc.2020.10.475
dc.description.abstractBackground In the TNT trial of triple negative breast cancer (NCT00532727), germline BRCA1/2 mutations were present in 28% of carboplatin responders. We assessed quantitative measures of structural chromosomal instability (CIN) to identify a wider patient subgroup within TNT with preferential benefit from carboplatin over docetaxel.Patients and methods Copy number aberrations (CNAs) were established from 135 formalin-fixed paraffin-embedded primary carcinomas using Illumina OmniExpress SNP-arrays. Seven published [allelic imbalanced CNA (AiCNA); allelic balanced CNA (AbCNA); copy number neutral loss of heterozygosity (CnLOH); number of telomeric allelic imbalances (NtAI); BRCA1-like status; percentage of genome altered (PGA); homologous recombination deficiency (HRD) scores] and two novel [Shannon diversity index (SI); high-level amplifications (HLAMP)] CIN-measurements were derived. HLAMP was defined based on the presence of at least one of the top 5% amplified cytobands located on 1q, 8q and 10p. Continuous CIN-measurements were divided into tertiles. All nine CIN-measurements were used to analyse objective response rate (ORR) and progression-free survival (PFS).Results Patients with tumours without HLAMP had a numerically higher ORR and significantly longer PFS in the carboplatin (C) than in the docetaxel (D) arm [56% (C) versus 29% (D), P HLAMP,quiet  = 0.085; PFS 6.1 months (C) versus 4.1 months (D), P interaction/HLAMP  = 0.047]. In the carboplatin arm, patients with tumours showing intermediate telomeric NtAI and AiCNA had higher ORR [54% (C) versus 20% (D), P NtAI,intermediate  = 0.03; 62% (C) versus 33% (D), P AiCNA,intermediate  = 0.076]. Patients with high AiCNA and PGA had shorter PFS in the carboplatin arm [3.4 months (high) versus 5.7 months (low/intermediate); and 3.8 months (high) versus 5.6 months (low/intermediate), respectively; P interaction/AiCNA  = 0.027, P adj.interaction/AiCNA  = 0.125 and P interaction/PGA  = 0.053, P adj.interaction/PGA  = 0.176], whilst no difference was observed in the docetaxel arm.Conclusions Patients with tumours lacking HLAMP and demonstrating intermediate CIN-measurements formed a subgroup benefitting from carboplatin relative to docetaxel treatment within the TNT trial. This suggests a complex and paradoxical relationship between the extent of genomic instability in primary tumours and treatment response in the metastatic setting.
dc.formatPrint-Electronic
dc.format.extent58 - 65
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectChromosomal Instability
dc.subjectTrinitrotoluene
dc.subjectCarboplatin
dc.subjectAntineoplastic Combined Chemotherapy Protocols
dc.subjectPhenotype
dc.subjectTriple Negative Breast Neoplasms
dc.subjectBiomarkers
dc.titleAssessment of structural chromosomal instability phenotypes as biomarkers of carboplatin response in triple negative breast cancer: the TNT trial.
dc.typeJournal Article
dcterms.dateAccepted2020-10-13
rioxxterms.versionofrecord10.1016/j.annonc.2020.10.475
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by-nc-nd/4.0
rioxxterms.licenseref.startdate2021-01
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfAnnals of oncology : official journal of the European Society for Medical Oncology
pubs.issue1
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/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Trials & Statistics Unit
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Genomic Analysis – Clinical Trials
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/Clinical Trials & Statistics Unit
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Genomic Analysis – Clinical Trials
pubs.publication-statusPublished
pubs.volume32
pubs.embargo.termsNot known
icr.researchteamClinical Trials & Statistics Uniten_US
icr.researchteamGenomic Analysis – Clinical Trialsen_US
dc.contributor.icrauthorCheang, Chonen
dc.contributor.icrauthorBliss, Judithen
dc.contributor.icrauthorTutt, Andrewen


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