Adeyelu, Tolulope Tosin

5022 Background: Racial disparities are evident in PCa, with Black men experiencing a higher incidence and worse survival compared to NHW patients (pts). The molecular alterations that distinguish these groups remain incompletely characterized. Herein, we investigate the clinical-genomic features that potentially contribute to the differences in outcomes between Black and NHW pts with PCa. Methods: Comprehensive next-generation sequencing of DNA (592-gene panel/whole exome) and RNA (whole transcriptome) was performed at Caris Life Sciences on PCa tissue samples (n = 5,412), collected from 2015 to 2023. Transcriptomic signatures – Androgen Receptor (AR), Neuroendocrine PCa (NEPC) scores – were calculated. Real-world overall survival (OS) data was obtained from insurance claims and was analyzed using Kaplan-Meier estimation. Results: Overall, 1,078 pts with PCa identified as Black, while 4,334 were NHW. Black pts were younger at biopsy collection than NHW pts (median age 66 vs 71 years, P < 0.001). The proportion of metastatic samples was higher in Black pts compared to NHW pts (43% vs 38%, P < 0.01). The prevalence of castrated PCa specimens was similar between Black and NHW pts (26.0% vs 25.4%, P = 0.72). Among non-castrated PCa tumors, tumors from NHW pts had more frequent alterations in TP53 , PTEN , PIK3CA , and CHEK2 , while tumors from Black pts had more SPOP and CTNNB1 mutations. In the castrate setting, TP53 and PTEN alterations were more frequent in tissue samples from NHW pts, while CDK12 and SPOP mutations were more frequent in tumors from Black pts. TMPRSS2 fusions were more prevalent in the NHW cohort across both castrated and non-castrated tumors. Tumors from Black pts had higher FOLH1 / PSMA and STEAP1 expression, elevated AR scores, but lower CD276 / B7H3 expression and NEPC scores. In the overall cohort, Black pts demonstrated a shorter median OS from diagnosis compared to NHW pts (86 vs 94 mos, P = 0.03). Black pts had a significantly longer time on treatment with enzalutamide in both the non-castrate (HR 0.82, P= 0.04) and castrate subgroups (HR 0.77, P= 0.03). Among pts with homologous recombination repair (HRR) deficiency-harboring tumors, PARP inhibitors provided a numerically longer survival benefit in Black pts than in NHW pts (21 vs 13 mos, P = 0.09). Conclusions: This multi-institutional study reveals distinct molecular profiles between Black and NHW pts with PCa. Despite having molecular features associated with better prognosis, Black men demonstrated worse survival outcomes, pointing to multifaceted determinants of disease outcomes. Notably, Black pts had improved outcomes on enzalutamide and showed potential benefit from PARP inhibitors in the presence of HRR mutations. These findings highlight genomic differences in diverse PCa populations and suggest therapeutic opportunities to address outcome disparities.

4568 Background: The 2IR immune response score was initially developed using bulk RNA sequencing of pre-treatment tissue from ImVigor 210 and CheckMate 275 trials, however these trials enrolled patients (pts) with pure urothelial carcinoma (pUC) histology. Patients with hsUC often exhibit worse response to immune checkpoint inibitors (ICI) than patients with pUC. Here, we evaluated the 2IR score as a prognostic or predictive biomarker in real-world pts with hsUC. Methods: Specimens from pts with pUC (n = 1677) and hsUC (n = 417) were profiled at Caris Life Sciences (Phoenix, AZ) using next generation sequencing (NGS) of DNA and RNA. HsUC histologies included majority ( > 50%) squamous (n = 340), sarcomatoid (n = 51), neuroendocrine (n = 20), and micropapillary (n = 6) component. 2IR was calculated by comparative RNA expression of 10 adaptive immune genes and 39 pro-tumorigenic genes. Tumors were classified as 2IR-Low (2IR ≤ -0.5), -Mid (-0.5 < 2IR < 0), and -High (2IR ≥ 0), as previously described (Wang et al., 2022). Spearman correlation analysis was utilized to compare 2IR with tumor mutation burden (TMB), interferon score (IFN) and the tumor microenvironment (TME) cell fractions estimated using quanTIseq. Clinical outcomes included real-world overall survival (rwOS) from ICI start to last contact and time on treatment (ToT) with pembrolizumab, obtained via matched insurance claims data and calculated using Kaplan-Meier methods, while Hazard ratio (HR) was calculated by Cox proportional model. Results: For patients with hsUC, distribution of 2IR score was High 5.76%, Mid 33.3%, and Low 60.9%. Median 2IR score was significantly lower in squamous (-0.60, p < 0.0001) and sarcomatoid UC (-0.82, p < 0.0001) compared to pUC (-0.41) and significantly higher in neuroendocrine UC (-0.15, p = 0.003). Among patients with hsUC, median rwOS was significantly longer for patients with high/mid 2IR score compared to low 2IR score (25.3 [10.9-39.3] months vs. 8.7 [6.2-11.3] months; HR 0.52, 95% CI 0.34 – 0.78, p = 0.0017). ToT with pembrolizumab was also significantly longer for high/mid 2IR score compared to low 2IR score (3.0 [1.4-5.5] months vs. 2.1 [1.4-3.3] months; HR 0.68, 95% CI 0.46-1.00, p = 0.0471). Similar to pUC, 2IR score in patients with squamous UC was positively associated with CD8 T cell infiltration (r = 0.39; p < 0.0001), IFN score (r = 0.41, p < 0.0001), and TMB (r = 0.20, p < 0.001) and negatively associated with M1 macrophage infiltration (r = -0.25, p < 0.0001). 2IR scores in hsUC correlated positively but not significantly with mutations in TP53 (Median: -0.59 vs -0.62, p = 0.067) and PIK3CA (Median: -0.56 vs -0.61, p = 0.172) and negatively with mutations in CDKN2A (Median: -0.67 vs -0.59, p = 0.052). Conclusions: In a real-world cohort of patients with hsUC, we show the 2IR score may be prognostic for rwOS and predictive for pembrolizumab ToT. Prospective studies are needed to further validate this biomarker for use in this population.

Abstract Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive lung tumor marked by significant molecular heterogeneity. In a study of 590 patients across two independent cohorts, we observed comparable overall survival across treatment regimens (chemotherapy, chemoimmunotherapy, immunotherapy) without unexpected adverse events. Genomic analysis identified distinct NSCLC-like (KEAP1, KRAS, STK11 mutations) and SCLC-like (RB1, TP53 mutations) LCNEC subtypes, with 80% aligning with SCLC transcriptional profiles. Serial sampling revealed stable mutational but shifting transcriptomic landscapes over time. NSCLC-like LCNECs showed elevated FGL-1 (a LAG-3 ligand) and SPINK1 expression, while SCLC-like subtypes expressed higher levels of DLL3. Immunofluorescence confirmed FGL-1 in NSCLC-like LCNECs, and H&E slide analyses indicated fewer tumor-infiltrating lymphocytes in LCNECs versus other lung cancers. These findings highlight LCNEC’s distinct immunogenomic profile, supporting future investigations into LAG-3, SPINK1, and DLL3-targeted therapies.