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dc.contributor.authorRescigno, Pen_US
dc.contributor.authorGurel, Ben_US
dc.contributor.authorPereira, Ren_US
dc.contributor.authorCrespo, Men_US
dc.contributor.authorRekowski, Jen_US
dc.contributor.authorRediti, Men_US
dc.contributor.authorBarrero, Men_US
dc.contributor.authorMateo, Jen_US
dc.contributor.authorBianchini, Den_US
dc.contributor.authorMessina, Cen_US
dc.contributor.authorFenor de la Maza, MDen_US
dc.contributor.authorChandran, Ken_US
dc.contributor.authorCarmichael, Jen_US
dc.contributor.authorGuo, Cen_US
dc.contributor.authorPaschalis, Aen_US
dc.contributor.authorSharp, Aen_US
dc.contributor.authorSeed, Gen_US
dc.contributor.authorFigueiredo, Ien_US
dc.contributor.authorLambros, Men_US
dc.contributor.authorMiranda, Sen_US
dc.contributor.authorFerreira, Aen_US
dc.contributor.authorBertan, Cen_US
dc.contributor.authorRiisnaes, Ren_US
dc.contributor.authorPorta, Nen_US
dc.contributor.authorYuan, Wen_US
dc.contributor.authorCarreira, Sen_US
dc.contributor.authorde Bono, JSen_US
dc.date.accessioned2020-10-12T10:37:11Z
dc.date.issued2021-01en_US
dc.identifier.citationClinical cancer research : an official journal of the American Association for Cancer Research, 2021, 27 (2), pp. 566 - 574en_US
dc.identifier.issn1078-0432en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4139
dc.identifier.eissn1557-3265en_US
dc.identifier.doi10.1158/1078-0432.ccr-20-2371en_US
dc.description.abstract<h4>Purpose</h4>Cyclin-dependent kinase 12 (CDK12) aberrations have been reported as a biomarker of response to immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). Herein, we characterize CDK12-mutated mCRPC, presenting clinical, genomic, and tumor-infiltrating lymphocyte (TIL) data.<h4>Experimental design</h4>Patients with mCRPC consented to the molecular analyses of diagnostic and mCRPC biopsies. Genomic analyses involved targeted next-generation (MiSeq; Illumina) and exome sequencing (NovaSeq; Illumina). TILs were assessed by validated immunocytochemistry coupled with deep learning-based artificial intelligence analyses including multiplex immunofluorescence assays for CD4, CD8, and FOXP3 evaluating TIL subsets. The control group comprised a randomly selected mCRPC cohort with sequencing and clinical data available.<h4>Results</h4>Biopsies from 913 patients underwent targeted sequencing between February 2015 and October 2019. Forty-three patients (4.7%) had tumors with CDK12 alterations. CDK12-altered cancers had distinctive features, with some revealing high chromosomal break numbers in exome sequencing. Biallelic CDK12-aberrant mCRPCs had shorter overall survival from diagnosis than controls [5.1 years (95% confidence interval (CI), 4.0-7.9) vs. 6.4 years (95% CI, 5.7-7.8); hazard ratio (HR), 1.65 (95% CI, 1.07-2.53); <i>P</i> = 0.02]. Median intratumoral CD3<sup>+</sup> cell density was higher in CDK12 cancers, although this was not statistically significant (203.7 vs. 86.7 cells/mm<sup>2</sup>; <i>P</i> = 0.07). This infiltrate primarily comprised of CD4<sup>+</sup>FOXP3<sup>-</sup> cells (50.5 vs. 6.2 cells/mm<sup>2</sup>; <i>P</i> < 0.0001), where high counts tended to be associated with worse survival from diagnosis (HR, 1.64; 95% CI, 0.95-2.84; <i>P</i> = 0.077) in the overall population.<h4>Conclusions</h4>CDK12-altered mCRPCs have worse prognosis, with these tumors surprisingly being primarily enriched for CD4<sup>+</sup>FOXP3<sup>-</sup> cells that seem to associate with worse outcome and may be immunosuppressive.<i>See related commentary by Lotan and Antonarakis, p. 380</i>.en_US
dc.formatPrint-Electronicen_US
dc.format.extent566 - 574en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.titleCharacterizing CDK12-Mutated Prostate Cancers.en_US
dc.typeJournal Article
dcterms.dateAccepted2020-09-23en_US
rioxxterms.versionofrecord10.1158/1078-0432.ccr-20-2371en_US
rioxxterms.licenseref.startdate2021-01en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfClinical cancer research : an official journal of the American Association for Cancer Researchen_US
pubs.issue2en_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/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Biomarkers
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Cancer Biomarkers
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Trials & Statistics Unit
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/18/19 Starting Cohort
pubs.publication-statusPublisheden_US
pubs.volume27en_US
pubs.embargo.termsNot knownen_US
icr.researchteamCancer Biomarkersen_US
icr.researchteamClinical Trials & Statistics Uniten_US
icr.researchteamProstate Cancer Targeted Therapy Groupen_US
dc.contributor.icrauthorPorta, Nuriaen_US
dc.contributor.icrauthorDe Bono, Johannen_US
dc.contributor.icrauthorMiranda, Susanaen_US
dc.contributor.icrauthorCarreira, Suzanneen_US
dc.contributor.icrauthorRescigno, Pasqualeen_US


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