Show simple item record

dc.contributor.authorRescigno, P
dc.contributor.authorGurel, B
dc.contributor.authorPereira, R
dc.contributor.authorCrespo, M
dc.contributor.authorRekowski, J
dc.contributor.authorRediti, M
dc.contributor.authorBarrero, M
dc.contributor.authorMateo, J
dc.contributor.authorBianchini, D
dc.contributor.authorMessina, C
dc.contributor.authorFenor de la Maza, MD
dc.contributor.authorChandran, K
dc.contributor.authorCarmichael, J
dc.contributor.authorGuo, C
dc.contributor.authorPaschalis, A
dc.contributor.authorSharp, A
dc.contributor.authorSeed, G
dc.contributor.authorFigueiredo, I
dc.contributor.authorLambros, M
dc.contributor.authorMiranda, S
dc.contributor.authorFerreira, A
dc.contributor.authorBertan, C
dc.contributor.authorRiisnaes, R
dc.contributor.authorPorta, N
dc.contributor.authorYuan, W
dc.contributor.authorCarreira, S
dc.contributor.authorde Bono, JS
dc.date.accessioned2020-10-12T10:37:11Z
dc.date.issued2021-01
dc.identifier.citationClinical cancer research : an official journal of the American Association for Cancer Research, 2021, 27 (2), pp. 566 - 574
dc.identifier.issn1078-0432
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4139
dc.identifier.eissn1557-3265
dc.identifier.doi10.1158/1078-0432.ccr-20-2371
dc.description.abstractPurpose 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.Experimental design 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.Results 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); P = 0.02]. Median intratumoral CD3 + cell density was higher in CDK12 cancers, although this was not statistically significant (203.7 vs. 86.7 cells/mm 2 ; P = 0.07). This infiltrate primarily comprised of CD4 + FOXP3 - cells (50.5 vs. 6.2 cells/mm 2 ; P < 0.0001), where high counts tended to be associated with worse survival from diagnosis (HR, 1.64; 95% CI, 0.95-2.84; P = 0.077) in the overall population.Conclusions CDK12-altered mCRPCs have worse prognosis, with these tumors surprisingly being primarily enriched for CD4 + FOXP3 - cells that seem to associate with worse outcome and may be immunosuppressive. See related commentary by Lotan and Antonarakis, p. 380 .
dc.formatPrint-Electronic
dc.format.extent566 - 574
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleCharacterizing CDK12-Mutated Prostate Cancers.
dc.typeJournal Article
dcterms.dateAccepted2020-09-23
rioxxterms.versionofrecord10.1158/1078-0432.ccr-20-2371
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2021-01
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfClinical cancer research : an official journal of the American Association for Cancer Research
pubs.issue2
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/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.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-statusPublished
pubs.volume27
pubs.embargo.termsNot known
icr.researchteamCancer Biomarkersen_US
icr.researchteamClinical Trials & Statistics Uniten_US
icr.researchteamProstate Cancer Targeted Therapy Groupen_US
dc.contributor.icrauthorRescigno, Pasqualeen
dc.contributor.icrauthorPorta, Nuriaen
dc.contributor.icrauthorDe Bono, Johannen
dc.contributor.icrauthorMiranda, Susanaen
dc.contributor.icrauthorCarreira, Suzanneen


Files in this item

Thumbnail

This item appears in the following collection(s)

Show simple item record

https://creativecommons.org/licenses/by/4.0
Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by/4.0