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.
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.
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).
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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2026 Apr 21 [Epub ahead of print]
Allison Makovec, Ava P Gustafson, Nishant Gandhi, Swati Rampalli, Ali T Arafa, Andrew Elliott, Norm Smith, Martin Felices, Philippa R Kennedy, Eugene Shenderov, Akash Patnaik, Vivek Narayan, Elisabeth I Heath, Nicholas A Zorko, Xiaolei Shi, Emmanuel S Antonarakis, Rana R McKay, Justin Hwang
University of Kansas United States., University of Minnesota Minneapolis, MN United States., Caris Life Sciences (United States) Phoenix, AZ United States., University of Minnesota Minneapolis United States., Caris Life Sciences (United States) United States., University of Minnesota Minneapolis, Minnesota United States., Sidney Kimmel Comprehensive Cancer Center Baltimore, MD United States., University of Chicago Chicago, IL United States., University of Pennsylvania Philadelphia, Pennsylvania United States., Mayo Clinic Rochester, MN United States., University of Maryland Medical Center United States., University of California, San Diego La Jolla, CA United States.