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In Clinical cancer research : an official journal of the American Association for Cancer Research

PURPOSE : 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 data.

EXPERIMENTAL DESIGN : Patients with mCRPC consented to the molecular analyses of diagnostic and metastatic CRPC biopsies. Genomic analyses involved targeted next generation (MiSeqTM; Illumina) and exome sequencing (NovaSeqTM; Illumina). Tumor-infiltrating lymphocytes (TIL) 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 Feb/15 and Oct/19. 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 mCRPC had shorter overall survival from diagnosis than controls (5.1 years [95% CI: 4.0, 7.9] vs 6.4 years [95% CI: 5.7, 7.8]; 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 versus 86.7 cells/mm2, P=0.07). This infiltrate primarily comprised CD4+FOXP3- cells (50.5 versus 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.

Rescigno Pasquale, Gurel Bora, Pereira Rita, Crespo Mateus, Rekowski Jan, Rediti Mattia, Barrero Maialen, Mateo Joaquin, Bianchini Diletta, Messina Carlo, Fenor de la Maza M D, Chandran Khobe, Carmichael Juliet, Guo Christina, Paschalis Alec, Sharp Adam, Seed George, Figueiredo Ines, Lambros Maryou Bk, Miranda Susana, Ferreira Ana, Bertan Claudia, Riisnaes Ruth, Porta Nuria, Yuan Wei, Carreira Suzanne, de Bono Johann S