B7-H3 Gene Expression Shapes Prognosis and Therapeutic Opportunities across Patient Groups with Prostate Cancer.
High B7-H3 expression in hormone-sensitive prostate cancer is linked to worse overall survival, while in metastatic tumors, it may indicate better outcomes. These findings highlight the complexity of B7-H3 as a potential therapeutic target.
Where it sits
this study against the rest of the degarelix corpusSummary and findings
This study examined B7-H3 gene expression in 8,157 prostate cancer samples to evaluate its association with overall survival (OS) across different patient groups. High B7-H3 expression was linked to adverse OS in hormone-sensitive prostate cancer (HSPC) and primary tumors, while it was associated with favorable OS in metastatic tumors. The findings suggest B7-H3's potential as a therapeutic target, but no treatment claims are made.
Abstract
<h4>Purpose</h4>B7-H3 (CD276) 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.<h4>Experimental design</h4>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 (>75th percentile) or B7-H3-low (<25th percentile). The OS was evaluated using Kaplan-Meier and Cox proportional hazards models.<h4>Results</h4>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 and FOXA1), AR-associated pathogenic dysregulations (AR-V7, SPOP, FOXA1, and TMPRSS2:ERG fusions), and actionable surface antigens (TROP2 and NECTIN-4). Weak correlations were found for lineage-plastic program regulators (EZH2, SOX2, and ASCL1) and NEPC-associated surface antigens (DLL3 and CEACAM5). 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; q < 0.0001] although it was 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 the poorest survival in Asian/Pacific Islander patients with metastatic prostate cancer (HR, 3.72; CI, 1.49-9.29; q = 0.012).<h4>Conclusions</h4>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. See related article by Sharma et al., p. 3365.
Background
The study investigates the role of B7-H3 (CD276) in prostate cancer, particularly its expression levels and their implications for overall survival (OS). Previous research has indicated that B7-H3 may be a promising target for therapy in high-risk localized and treatment-refractory metastatic prostate cancer. Understanding the expression patterns of B7-H3 across different patient demographics and disease states is crucial for guiding therapeutic development.
Methods
The study analyzed a total of 8,157 prostate cancer samples with paired DNA/RNA, categorized by tissue site, self-reported race, and disease state: hormone-sensitive prostate cancer (HSPC), castration-resistant prostate cancer (CRPC), or neuroendocrine prostate cancer (NEPC). B7-H3 expression was classified into quartiles, with high expression defined as >75th percentile and low expression as <25th percentile. Overall survival was evaluated using Kaplan-Meier and Cox proportional hazards models.
Results
High B7-H3 expression in HSPCs was associated with an adverse OS (HR, 1.30; CI, 1.15-1.46; q < 0.0001). Similarly, high expression in primary tumors also indicated adverse OS (HR, 1.342; CI, 1.19-1.512; q < 0.0001). In contrast, high B7-H3 expression in metastatic tumors correlated with favorable OS (HR, 0.823; CI, 0.719-0.942; q = 0.0048). The study also found significant racial disparities in OS, particularly noting the poorest survival in Asian/Pacific Islander patients with metastatic prostate cancer (HR, 3.72; CI, 1.49-9.29; q = 0.012).
Interpretation
The findings suggest a complex role for B7-H3 in prostate cancer, with high expression correlating with poor outcomes in certain contexts while being favorable in others. This duality raises questions about the clinical significance of B7-H3 as a therapeutic target. The study's observational nature and lack of control for confounding variables limit the ability to draw definitive conclusions about causation. Practitioners should consider these factors when interpreting the results and their implications for treatment strategies.
Key findings
- High B7-H3 expression in HSPCs portended adverse OS (HR, 1.30; CI, 1.15-1.46; q < 0.0001).
- High B7-H3 expression in primary tumors portended adverse OS (HR, 1.342; CI, 1.19-1.512; q < 0.0001).
- High B7-H3 expression in metastatic tumors was associated with favorable OS (HR, 0.823; CI, 0.719-0.942; q = 0.0048).
- The poorest survival was observed in Asian/Pacific Islander patients with metastatic prostate cancer (HR, 3.72; CI, 1.49-9.29; q = 0.012).
- Weak correlations were found for lineage-plastic program regulators and NEPC-associated surface antigens.
Limitations
- Observational study design limits causal inferences.
- Did not account for treatment history or other clinical variables.
- Racial disparities in survival outcomes were noted but not fully explored.