Characterizing CDK12-Mutated Prostate Cancers
Pasquale Rescigno, Bora Gürel, Rita Pereira, Mateus Crespo, Jan Rekowski, Mattia Rediti, Maialen Barrero, Joaquı́n Mateo, Diletta Bianchini, Carlo Messina, Maria D. Fenor de la Maza, Khobe Chandran, Juliet Carmichael, Christina Guo, Alec Paschalis, Adam Sharp, George Seed, Ines Figueiredo, Maryou Lambros, Susana Miranda, Ana Ferreira, Cláudia Bertan, Ruth Riisnaes, Núria Porta, Wei Yuan, Suzanne Carreira, Johann S. de Bono
Abstract
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