3114 - Molecular and Immune Signatures of Early-Onset Prostate Cancer: Implications for Tumor Biology and Treatment Approaches
Presenter(s)
R. M. Narasimhan1, I. C. Ogobuiro2, S. Deshmukh3, U. Swami4, N. Agarwal5, R. R. Mckay6, M. C. Abramowitz7, A. Pollack7, A. Dal Pra7, S. Punnen8, and B. A. Mahal9; 1Department of Radiation Oncology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, 2Department of Radiation Oncology, University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL, 3Caris Life Sciences, Phoenix, AZ, 4Huntsman Cancer Institute, Salt Lake City, UT, 5Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 6University of California San Diego, La Jolla, CA, 7Department of Radiation Oncology, University of Miami/Sylvester Comprehensive Cancer Center, Miami, FL, 8University of Miami, Miami, FL, 9Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Department of Radiation Oncology, Boston, MA
Purpose/Objective(s):
The median onset age of prostate cancer (PC) is 66, yet incidence in men <55 years is increasing (Siegel et al., 2023). While early-onset PC (EOPC) is linked to hereditary factors and distinct molecular features, its full landscape and potential implications for tailored treatment modalities remain underexplored. This study characterizes the molecular and immune signatures of EOPC and average-onset PC.Materials/Methods:
We analyzed 5,305 PC samples (<55 yrs, n=575; =65 yrs, n=4,730) with next-generation sequencing (NGS; 592-gene panel, whole-exome sequencing [WES]) and whole-transcriptome sequencing (WTS) (Caris Life Sciences, Phoenix, AZ). Patients <55 years were classified as EOPC and those =65 years as AOPC. Microsatellite instability (MSI) was assessed via immunohistochemistry (IHC) and NGS, and tumor mutational burden (TMB) was defined as somatic mutations per tumor (high >10 mt/MB). Androgen receptor (AR) signaling and neuroendocrine PC (NEPC) scores came from predefined gene sets (Hieronymus et al., 2006; Beltran et al., 2016). Gene set enrichment analysis (GSEA) assessed pathway activation, and Quantiseq deconvolution estimated immune cell fractions. Chi-square and Mann-Whitney U tests determined statistical significance (p<0.05), with false discovery rate (FDR) correction (q<0.05).Results:
EOPC exhibited greater TMPRSS2 (35.8% vs. 29.7%), ETV1 (5.2% vs. 2.8%), ETV4 (3.4% vs. 1.6%), and BRAF (1.9% vs. 0.7%) fusions, but fewer APC (4% vs. 8%), CTNNB1 (2.4% vs. 4.6%), RB1 (2.3% vs. 4.7%), and AR (1% vs. 4.9%) mutations (p<0.05). TMB-high tumors (2.1% vs. 4.6%) and dMMR/MSI-H status (2.1% vs. 4%) were rarer in EOPC (p<0.05). EOPC exhibited higher myogenesis pathway activity (NES: 1.5, q<0.01) but comparable hedgehog (NES: 1.3, q=0.09) and epithelial-mesenchymal transition (NES: 1.3, q=0.09) activity. NEPC scores were higher in EOPC (0.359 vs. 0.353, q=0.04), along with increased MAPK pathway activation (3-fold, q=0.02). AR signature scores showed no significant difference (q=0.39), yet EOPC displayed higher PSA expression (1.2-fold, q<0.01) and increased immunomodulatory gene expression (IL12A, CTLA4, FC:1.2, q<0.05), with lower AR expression (1.3-fold, q<0.01). However, IHC-AR (q=1) and PD-L1 (q=0.57) levels were similar. EOPC had greater infiltration of NK cells (4.5% vs. 4.1%, q<0.01) and dendritic cells (1.9% vs. 1.8%, q<0.05).Conclusion:
EOPC is enriched for TMPRSS2, ETV1, ETV4, and BRAF fusions and exhibits distinct transcriptomic features, including higher NEPC scores, MAPK pathway activation, immunomodulatory gene expression, and increased NK and dendritic cell infiltration. These differences suggest distinct tumor biology, which may impact radiotherapeutic and immunotherapeutic treatment.