dc.contributor.author | Rescigno, P | |
dc.contributor.author | Gurel, B | |
dc.contributor.author | Pereira, R | |
dc.contributor.author | Crespo, M | |
dc.contributor.author | Rekowski, J | |
dc.contributor.author | Rediti, M | |
dc.contributor.author | Barrero, M | |
dc.contributor.author | Mateo, J | |
dc.contributor.author | Bianchini, D | |
dc.contributor.author | Messina, C | |
dc.contributor.author | Fenor de la Maza, MD | |
dc.contributor.author | Chandran, K | |
dc.contributor.author | Carmichael, J | |
dc.contributor.author | Guo, C | |
dc.contributor.author | Paschalis, A | |
dc.contributor.author | Sharp, A | |
dc.contributor.author | Seed, G | |
dc.contributor.author | Figueiredo, I | |
dc.contributor.author | Lambros, M | |
dc.contributor.author | Miranda, S | |
dc.contributor.author | Ferreira, A | |
dc.contributor.author | Bertan, C | |
dc.contributor.author | Riisnaes, R | |
dc.contributor.author | Porta, N | |
dc.contributor.author | Yuan, W | |
dc.contributor.author | Carreira, S | |
dc.contributor.author | de Bono, JS | |
dc.date.accessioned | 2020-10-12T10:37:11Z | |
dc.date.issued | 2020-09-28 | |
dc.identifier.citation | Clinical cancer research : an official journal of the American Association for Cancer Research, 2021, 27 (2), pp. 566 - 574 | |
dc.identifier.issn | 1078-0432 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4139 | |
dc.identifier.eissn | 1557-3265 | |
dc.identifier.doi | 10.1158/1078-0432.ccr-20-2371 | |
dc.description.abstract | PURPOSE: 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/mm2; P = 0.07). This infiltrate primarily comprised of CD4+FOXP3- cells (50.5 vs. 6.2 cells/mm2; 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.format | Print-Electronic | |
dc.format.extent | 566 - 574 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.title | Characterizing CDK12-Mutated Prostate Cancers. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2020-09-23 | |
rioxxterms.versionofrecord | 10.1158/1078-0432.ccr-20-2371 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2021-01 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Clinical cancer research : an official journal of the American Association for Cancer Research | |
pubs.issue | 2 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 27 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Cancer Biomarkers | |
icr.researchteam | Clinical Trials & Statistics Unit | |
icr.researchteam | Prostate Cancer Targeted Therapy Group | |
dc.contributor.icrauthor | Rescigno, Pasquale | |
dc.contributor.icrauthor | Gurel, Bora | |
dc.contributor.icrauthor | Pereira, Ana Rita | |
dc.contributor.icrauthor | Carmichael, Juliet | |
dc.contributor.icrauthor | Guo, Wei Yu | |
dc.contributor.icrauthor | Paschalis, Alec | |
dc.contributor.icrauthor | Sharp, Adam | |
dc.contributor.icrauthor | Seed, George | |
dc.contributor.icrauthor | Miranda, Susana | |
dc.contributor.icrauthor | Porta, Nuria | |
dc.contributor.icrauthor | Carreira, Suzanne | |
dc.contributor.icrauthor | De Bono, Johann | |