Clinical features and prognostic value of CDK12 mutation in prostate cancer patients.

103 Background: Studies have reported that biallelic loss of CDK12 in prostate cancer patients leads to genomic instability and an increase in tandem duplications. However, the prognostic relevance of CDK12 mutations has not been fully validated. Therefore, we assessed the clinical characteristics and outcomes of prostate cancer patients with CDK12 mutations, comparing this genomic subtype with prostate cancer lacking any genetic alterations. Methods: A total of 141 prostate cancer patients diagnosed between November 2010 and March 2024 were included. Genomic characteristics of biopsy tissues or plasma ctDNA were analyzed using next-generation sequencing to identify patients with CDK12 mutations and those without any genetic mutations. Due to the low incidence of biallelic CDK12 loss in this patient cohort, we integrated data from metastatic tumor biopsies and liquid biopsies. Notably, cfDNA and prostate cancer tumor biopsies from the same individuals have shown strong concordance in identifying somatic alterations. Results: We evaluated the clinical characteristics of the two groups of prostate cancer patients, and patients with CDK12 mutations were more aggressive and had a higher proportion of initial metastasis [77.05% (47/61) vs. 56.67% (51/80), P=0.013]. The median PSA at diagnosis was higher (60.63ng/ml vs. 38.02ng/ml), and the proportion of pathological Gleason score ≥8 was higher (85.25% (52/61) vs. 60.00% (48/80), P < 0.01). Patients with localized CDK12 mutations had shorter time to metastasis (median 34.10 months vs. 56.22 months, p < 0.001) and shorter survival than those without deleterious genetic alterations. Patients with CDK12 mutations had shorter median progression-free survival with conventional androgen-deprivation therapy, abiraterone, and docetaxel than those without deleterious mutations. However, the use of novel anti-male therapy, PARPi, immunotherapy or focal ablation can still prolong the survival of patients. Conclusions: CDK12 mutations are associated with metastasis and higher pathological malignancy, and they also serve as a predictive factor for poor clinical outcomes in patients receiving standard androgen deprivation therapy, abiraterone, or docetaxel treatment. Therefore, prostate cancer patients with CDK12 mutations may need to consider novel anti-androgen therapies, or combined interventions such as PARP inhibitors, immunotherapy, or focal treatments. This study underscores the importance of molecular diagnostics and the necessity of employing appropriate therapeutic strategies for CDK12-mutated prostate cancer. Overall, given the significant heterogeneity in clinical behavior, our research highlights the importance of this molecular subtype in prostate cancer and serves as a foundation for future prospective studies to further characterize the CDK12 subtype in prostate cancer.