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

<jats:p>&lt;div&gt;Abstract Purpose:&lt;p&gt;B7-H3 (&lt;i&gt;CD276&lt;/i&gt;) represents a promising therapeutic target tested in high-risk localized and treatment-refractory metastatic prostate cancer. 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.&lt;/p&gt; Experimental Design:&lt;p&gt;A total of 8,157 prostate cancer samples with paired DNA/RNA were analyzed based on annotations by tissue site, self-reported race, and disease state: hormone-sensitive prostate cancer (HSPC), castration-resistant prostate cancer (CRPC), or neuroendocrine prostate cancer (NEPC). Expression quartiles were B7-H3–high (&gt;75th percentile) or B7-H3–low (&lt;25th percentile). The OS was evaluated using Kaplan–Meier and Cox proportional hazards models.&lt;/p&gt; Results:&lt;p&gt;B7-H3 expression was broadly maintained but varied by tumor site, hormone sensitivity status, and race. High expression aligned with AR-associated transcription factors (&lt;i&gt;HOXB13&lt;/i&gt; and &lt;i&gt;FOXA1&lt;/i&gt;), AR-associated pathogenic dysregulations (AR-V7, &lt;i&gt;SPOP&lt;/i&gt;, &lt;i&gt;FOXA1&lt;/i&gt;, and &lt;i&gt;TMPRSS2:ERG&lt;/i&gt; fusions), and actionable surface antigens (TROP2 and NECTIN-4). Weak correlations were found for lineage-plastic program regulators (&lt;i&gt;EZH2&lt;/i&gt;, &lt;i&gt;SOX2&lt;/i&gt;, and &lt;i&gt;ASCL1&lt;/i&gt;) and NEPC-associated surface antigens (&lt;i&gt;DLL3&lt;/i&gt; and &lt;i&gt;CEACAM5&lt;/i&gt;). High B7-H3 expression in primary tumors and HSPCs portended adverse OS [hazard ratio (HR), 1.342 and 1.30; confidence interval (CI), 1.19–1.512 and 1.15–1.46; &lt;i&gt;q&lt;/i&gt; &lt; 0.0001] although it was favorable in metastatic tumors (HR, 0.823; CI, 0.719–0.942; &lt;i&gt;q&lt;/i&gt; = 0.0048). No significant differences in OS were observed among CRPCs and NEPCs, although OS varied by race, with the poorest survival in Asian/Pacific Islander patients with metastatic prostate cancer (HR, 3.72; CI, 1.49–9.29; &lt;i&gt;q&lt;/i&gt; = 0.012).&lt;/p&gt; Conclusions:&lt;p&gt;Maintained B7-H3 expression in various prostate cancer settings supports its viability as a target. The associations with AR-related molecular factors, surface antigens, and investigative targets for cell therapy or antibody–drug conjugates suggest potential dual-targeting strategies.&lt;/p&gt;&lt;p&gt;&lt;a target="_blank" href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-26-0642R2"&gt;&lt;i&gt;See related article by Sharma et al., p. 3365&lt;/i&gt;&lt;/a&gt;&lt;/p&gt;&lt;/div&gt;</jats:p>