Abstract A041: Profiling DNA damage response and immune checkpoint proteins in metastatic prostate cancer: Unraveling mechanisms of progression and therapeutic potential

Abstract Prostate cancer (PCa) frequently harbors genomic alterations in DNA Damage Response (DDR) genes, with up to 25% of metastatic cases exhibiting DDR mutations, primarily in the Homologous Recombination Repair (HRR) and Mismatch Repair (MMR) pathways. Additionally, Programmed Death-Ligand 1 (PDL-1), an immune checkpoint protein, plays a pivotal role in immune evasion, particularly in Metastatic Castration-Resistant Prostate Cancer (mCRPC). Despite their critical impact, the connection between DDR mutations and PDL-1 expression in mPCa remains underexplored. This study aims to uncover this vital relationship by assessing DDR protein expression and PDL-1 in a cohort of mPCa cases. We analyzed 50 mPCa patients using FFPE tissue blocks retrieved from archives to evaluate DDR proteins (BRCA1, BRCA2, ATM, CDK12, MLH1, and MSH2) and PDL-1 through a standardized immunohistochemistry (IHC) protocol. Protein expression was quantified based on staining intensity and the percentage of positive cells, while PDL-1 expression was assessed using the CPS score (≥1%). Statistical analysis included the Student’s t-test to evaluate associations and Pearson’s chi-square test to explore relationships between protein expression and clinicopathological parameters. Statistical significance was set at P < 0.05 with a 95% confidence interval. BRCA2 expression was significantly elevated compared to BRCA1 (P < 0.01) across all Gleason grades. ATM expression showed a moderate correlation with Gleason scores >4. Furthermore, loss of MLH1 and MSH2 was more frequently observed in cases with Gleason scores >4. No significant differences in CDK12 expression were found across the Gleason grades. PDL-1 expression was detected in 42% of cases (21/50), primarily in patients with metastatic castration-resistant prostate cancer (mCRPC). Notably, BRCA1 positivity exhibited a strong correlation with higher Gleason scores (R2 = 0.75, P < 0.001). In conclusion, BRCA1 expression is strongly associated with higher Gleason scores, while loss of MMR proteins is commonly observed in cases with higher Gleason scores. CDK12 expression shows no significant variation across Gleason grades. These findings highlight the potential of targeting DDR pathways and immune checkpoints as a promising strategy for developing more effective therapies for prostate cancer. Citation Format: Himanshu Himanshu, Seema Kaushal, Amlesh Seth, Atul Batra, Ranjit Kumar Sahoo, Brusabhanu Nayak, Riyaz Ahmad Mir, Asit Ranjan Mridha. Profiling DNA damage response and immune checkpoint proteins in metastatic prostate cancer: Unraveling mechanisms of progression and therapeutic potential [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A041.