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Characterizing CDK12-mutated prostate cancers A C

Lookup NU author(s): Dr Pasquale RescignoORCiD

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Abstract

2020 American Association for Cancer Research. 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 immuno-fluorescence 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 ¼ 0.02]. Median intratumoral CD3þ cell density was higher in CDK12 cancers, although this was not statistically significant (203.7 vs. 86.7 cells/mm2; P ¼ 0.07). This infiltrate primarily comprised of CD4þFOXP3 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 ¼ 0.077) in the overall population. Conclusions: CDK12-altered mCRPCs have worse prognosis, with these tumors surprisingly being primarily enriched for CD4þFOXP3 cells that seem to associate with worse outcome and may be immunosuppressive.

Publication metadata

Author(s): 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

Publication type: Article

Publication status: Published

Journal: Clinical Cancer Research

Year: 2021

Volume: 27

Issue: 2

Pages: 566-574

Print publication date: 15/01/2021

Online publication date: 19/01/2021

Acceptance date: 23/09/2020

ISSN (print): 1078-0432

ISSN (electronic): 1557-3265

Publisher: American Association for Cancer Research Inc.

URL: https://doi.org/10.1158/1078-0432.CCR-20-2371

DOI: 10.1158/1078-0432.CCR-20-2371

PubMed id: 32988971

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