Patient: 70-year-old male with metastatic prostate adenocarcinoma (T3bN3M1), Gleason score 9 (5+4), with seminal vesicle invasion, bladder wall infiltration, and necrotic pelvic lymph nodes.
Clinical Testing:
Alterations:
- TMPRSS2–ERG fusion (RNA, pathogenic)
- ERG overexpression (RNA, pathogenic)
- FOXA1 overexpression (RNA, pathogenic)
- CHD4 (p.R1340H), SMARCA4 (p.R448H), DICER1 (p.D1709G) (DNA; VUS)
Additional Biomarkers:
- MSI-High
- MMR deficiency: Loss of MSH2/MSH6 (IHC)
- PD-L1 positive: CPS = 20 (tissue & circulating tumor cells)
- HRD: Low
Genes / Pathways Affected:
- Androgen receptor (AR) signaling
- PI3K pathway
- Chromatin remodeling
- DNA mismatch repair (MMR) / immune response pathways
Treatment Options:
- Second-generation AR inhibitors (enzalutamide, abiraterone) due to TMPRSS2–ERG fusion and FOXA1-driven AR activation
- Immunotherapy (pembrolizumab, nivolumab) based on MSI-High and PD-L1 positivity
- Clinical-trial–based combinations targeting AR variants, chromatin regulators, and immune checkpoints
- Serial liquid biopsy monitoring to guide therapy adaptation
Indication:
Metastatic, high-grade prostate adenocarcinoma with aggressive biology, AR-driven disease, and concurrent immunogenic phenotype.
Research Findings:
Multi-omic DNA, RNA, and IHC profiling identified dual oncogenic drivers (TMPRSS2–ERG fusion and FOXA1 overexpression) responsible for AR pathway activation and potential resistance to conventional androgen deprivation therapy. Concurrent MMR deficiency (MSH2/MSH6 loss), MSI-High status, and PD-L1 positivity reveal a highly immunogenic tumor subset suitable for immune checkpoint inhibition. Low HRD and TMB excluded PARP inhibitor benefit, underscoring the value of integrated multi-omic profiling in defining personalized, pathway-directed treatment strategies.