Abstract 38P
Background
A hallmark of Prostate cancer (PCa) is the presence of genomic alterations in DNA Damage Response (DDR) genes, with up to 25% of metastatic cases exhibiting DDR mutations. These mutations primarily affect the Homologous Recombination Repair (HRR) and Mismatch Repair (MMR) pathways. Additionally, Programmed Death-Ligand 1 (PDL-1), an immune checkpoint protein, is associated with immune evasion mechanisms, particularly in Metastatic Castration-Resistant Prostate Cancer (mCRPC). There is sparse literature that integrates the evaluation of both DDR mutations and PDL-1 expression in metastatic Prostate cancer (mPCa). In this study, we aim to evaluate the expression of DDR protein and PDL-1 in a cohort of mPCa.
Methods
We evaluated 50 mPCa patients, and FFPE blocks were retrieved from the archives to assess DDR proteins (BRCA1, BRCA2, ATM, CDK12, MLH1, and MSH2) and PDL-1, using a standard immunohistochemistry (IHC) protocol. Protein expression was quantified based on the percentage of positive cells and staining intensity while PDL-1 was assessed using CPS score (≥1%). Statistical analysis used Student’s t-test to assess associations, and Pearson’s chi-square test examined the relationship between protein expression and clinicopathological parameters. Significance was set at P < 0.05 with a 95% confidence interval.
Results
BRCA2 expression was significantly higher than BRCA1 (P < 0.01) across all the Gleason grades. ATM expression showed a moderate correlation with Gleason grades >4. Additionally, the loss of MLH1 and MSH2 was more frequently identified in cases with Gleason scores >4. No significant differences were noted for CDK12 expression across Gleason groups. PDL-1 was seen in 20% of the cases (10/50), predominantly in patients with mCRPC. BRCA1 positivity strongly correlated with higher Gleason scores (R2 = 0.75, P < 0.001).
Conclusions
BRCA1 is strongly correlated with higher Gleason scores, while MMR protein loss is frequently observed in higher Gleason score cases. CDK12 shows no significant variation. These findings underscore the potential of targeting DDR pathways and immune checkpoints to develop more effective prostate cancer therapies.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.