Characterizing CDK12-Mutated Prostate Cancers.
Fenor de la Maza, MD
de Bono, JS
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<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>.
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Clinical Trials & Statistics Unit
Prostate Cancer Targeted Therapy Group
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Clinical cancer research : an official journal of the American Association for Cancer Research, 2021, 27 (2), pp. 566 - 574