Characterizing CDK12-Mutated Prostate Cancers.
View/ Open
Date
2020-09-28ICR Author
Author
Rescigno, P
Gurel, B
Pereira, R
Crespo, M
Rekowski, J
Rediti, M
Barrero, M
Mateo, J
Bianchini, D
Messina, C
Fenor de la Maza, MD
Chandran, K
Carmichael, J
Guo, C
Paschalis, A
Sharp, A
Seed, G
Figueiredo, I
Lambros, M
Miranda, S
Ferreira, A
Bertan, C
Riisnaes, R
Porta, N
Yuan, W
Carreira, S
de Bono, JS
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Research team
Cancer Biomarkers
Clinical Trials & Statistics Unit
Prostate Cancer Targeted Therapy Group
Language
eng
Date accepted
2020-09-23
License start date
2021-01
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2021, 27 (2), pp. 566 - 574
Publisher
AMER ASSOC CANCER RESEARCH