5536 Background: Prostate cancer (PCa) brain metastasis (BM) is a rare event occurring in 0.16-0.63% of PCa patients. Current clinical data on this phenomenon is limited to small retrospective cohorts and our understanding of it is incomplete. We sought to identify clinical and molecular predictors of PCa BM in a large retrospective cohort treated at our institution. Methods: Men diagnosed with Pca from 1995-2017 with ≥6 months of follow-up were included. Data was collected on clinical and tumor characteristics at diagnosis, PCa treatment, brain and bone metastasis, and tumor genetic profile based on Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT) analysis. Results were examined using Kyoto Encyclopedia of Genes and Genome (KEGG) pathway. Genes altered in ≥5% of patients were included. Time to brain metastasis (TTBM) and overall survival (OS) were analyzed with univariable (UVA) Fine-Gray competing risks regression and Cox proportional hazards. TTBM and OS were landmarked at 6 months after PCa diagnosis. False discovery rate (FDR) adjustment accounted for multiple comparisons. Results: 27,887 men met inclusion criteria; 74 developed BM. Clinical variables associated with increased hazard of TTBM in UVA were high-clinical and pathologic-* (p<.001) T stage, node-positive disease* (p<.001), primary* and total* Gleason (p<.001), receipt of abiraterone* (HR 52.51 (95% CI 7.1-389.8), p<.001), and receipt of leuprolide* (HR 3.0 (95% CI 1.7-5.4), p<.001). Tumor alterations associated with BM include mutations in BRCA2 (HR 2.94 (95% CI 1.1-8.0), p=.04), MYC (HR 3.41 (95% CI 1.2-9.5), p=.02), PTEN (HR 2.90 (95% CI 1.2-6.9), p=.02), RB1 (HR 3.09 (95% CI 1.2-8.0), p=.02), and pathways involving homologous recombination (HR 2.70 (95% CI 1.1-6.4), p=.02), Fanconi anemia* (HR 4.22 (95% CI 1.8-10.0), p<.001), Ras signaling* (HR 4.6 (95% CI 1.5-13.9), p=.006), mTOR signaling (HR 2.88 (95% CI 1.1-7.9), p=.04), VEGF signaling* (HR 3.60 (95% CI 1.5-8.8), p=.005), and GnRH signaling* genes (HR 3.93 (95% CI 1.6-9.6), p0.003). Variables associated with increased hazard of BM after FDR adjustment are denoted with an asterisk. Variables associated with reduced OS after FDR adjustment were neuroendocrine or blastoma histology, node-positive disease, high-T stage, high initial PSA, receipt of leuprolide, and alterations in AR, TP53, and CDK12 genes. Conclusions: PCa BM is significantly associated with high-stage and grade disease, receipt of androgen deprivation agents such as abiraterone and leuprolide, and alterations in the Fanconi anemia, Ras, VEGF, and GnRH pathways.
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