Clinical and genomic correlates of brain metastases in small cell carcinoma of the bladder.

807 Background: Small cell carcinoma of the bladder (SCCB) is a rare but aggressive subtype with a ~10% cumulative incidence of brain metastases (BM), markedly higher than in urothelial carcinoma (~1%). Patients with metastatic SCCB have a median overall survival (OS) of ~13 months, with expected worse prognosis after BM diagnosis. We aimed to identify clinical and genomic correlates of central nervous system (CNS) tropism in SCCB. Methods: We retrospectively analyzed 236 patients with metastatic SCCB treated at MD Anderson Cancer Center between 1992–2024. Patients who underwent brain MRI or contrast-enhanced CT were included and categorized as BM (n = 43) or no-BM (n = 99). Next-generation sequencing (NGS) was performed under CLIA-certified assays when available. Results: Among 142 evaluable patients, 43 (30.3%) developed BM; most were asymptomatic (67.4%) at diagnosis. Median survival after BM was 7.6 months (95% CI 4.7–9.1). Local CNS therapy was administered in 67.4% and systemic therapy in 55.8%. Within the metachronous metastatic cohort, BM occurred in 23 of 60 (38.3%) patients with ≤cT2 N0 disease and 11 of 23 (47.8%) with ≥cT3 or N+ disease. The odds ratio for higher versus lower stage was 1.47 (95% CI 0.56–3.89), indicating a statistically inconclusive association. Among patients who initially had localized disease, we did not observe higher odds of prior neoadjuvant chemotherapy among those who developed brain metastases compared with those who did not (OR 1.03, 95% CI 0.40–2.67, p = 0.95). On multivariable analysis adjusted for clinical stage, patients with pure small cell histology had greater odds of developing BM compared with those with mixed histology (OR 2.34, 95% CI 1.05–5.22, p = 0.038). Genomic data were available for 46 patients (16 BM; 30 no BM). Frequent alterations included TP53 (87%), TERT (46%), RB1 (41%), PIK3CA (24%), and ARID1A (20%). PIK3CA mutations were enriched among BM patients (43.8% vs 13.3%, OR 5.1, p = 0.03). Conclusions: Brain metastases were observed across a range of initial clinical stages among patients who later developed metastatic SCCB, supporting consideration of baseline MRI surveillance at diagnosis. PIK3CA alterations were enriched in BM, suggesting a potential biological role in CNS tropism. These findings justify translational studies of PI3K signaling and ongoing preclinical work testing brain-penetrant PI3K inhibitors in this disease. Variable, n (%) BM (n=43) No BM (n=99) p -value Sex, Male 30 (69.8%) 83 (83.8%) 0.071 Onset of metastasis Synchronous 9 (20.9%) 50 (50.5%) 0.001 Metachronous 34 (79.1%) 49 (49.5%) Histology Pure small cell 19 (44.2%) 30 (30.3%) 0.127 Mixed small cell (with UC) 24 (55.8%) 69 (69.7%) TNM at diagnosis T1N0M0 3 (7%) 5 (5.1%) 0.616 T2N0M0 20 (46.5%) 37 (37.4%) T3/4N0M0 7 (16.3%) 13 (13.1%) Any T, N+, M0 4 (9.3%) 13 (13.1%) Any T, Any N, M+ 9 (20.9%) 31 (31.3%) PCI History 4 (9.3%) 20 (20.2%) 0.145 Neoadjuvant Chemotherapy 25 (58.1%) 38 (31.3%) 0.91