B7-H3 Gene Expression Shapes Prognosis and Therapeutic Opportunities across Patient Groups with Prostate Cancer

PURPOSE: B7-H3 (CD276) represents a promising therapeutic target tested in high-risk localized and treatment-refractory metastatic prostate cancer (PC). To guide therapeutic development and treatment strategies, we examined prostate tumors and evaluated expression, molecular features, and overall survival (OS), accounting for tissue site, hormone-sensitivity status, and race. EXPERIMENTAL DESIGN: 8,157 PC samples with paired DNA/RNA were analyzed based on annotations by tissue site, self-reported race, and disease state: hormone-sensitive (HSPC), castration-resistant (CRPC), or neuroendocrine PC (NEPC). Expression quartiles were B7-H3-high (>75th percentile) or B7-H3-low (<25th percentile). OS was evaluated using Kaplan-Meier and Cox proportional hazards models. RESULTS: B7-H3 expression was broadly maintained but varied by tumor site, hormone-sensitivity status, and race. High expression aligned with AR-associated transcription factors (HOXB13, FOXA1), AR-associated pathogenic dysregulations (AR-V7, SPOP, FOXA1, TMPRSS2:ERG fusions), and actionable surface antigens (TROP2, NECTIN-4). Weak correlations were found for lineage-plastic program regulators (EZH2, SOX2, ASCL1) and NEPC-associated surface antigens (DLL3, CEACAM5). High B7-H3 expression in primary tumors and HSPCs portended adverse OS (HR: 1.342, 1.30, CI: 1.19-1.512, 1.15-1.46, q < 0.0001), although favorable in metastatic tumors (HR: 0.823, CI: 0.719-0.942, q = 0.0048). No significant differences in OS were observed among CRPCs and NEPCs, although OS varied by race, with poorest survival in Asian/Pacific Islander metastatic PC patients (HR = 3.72, CI: 1.49-9.29, q = 0.012). CONCLUSIONS: Maintained B7-H3 expression in various PC settings supports its viability as a target. Associations with AR-related molecular factors, surface antigens, and investigative targets for cell therapy or antibody-drug conjugates (ADC) suggest potential dual-targeting strategies.