Objectives/Goals: The impact of genetic alterations on survival in patients with neuroendocrine prostate cancer (NEPC) is unclear. This study assessed how genetic alterations and tumor mutational burden (TMB) affect overall survival (OS) in patients with NEPC treated at Mayo Clinic. Methods/Study Population: Demographic, clinicopathologic, and genomic data from patients with NEPC treated at Mayo Clinic (2015–2025) were abstracted from electronic medical records. Patients had consented to research and received at least one cycle of therapy. Descriptive statistics summarized patient characteristics, and survival was estimated with Kaplan–Meier analysis. OS was compared by disease type (de novo vs treatment-emergent NEPC), TMB (high vs low), and RB1, TP53, and PTEN alteration status. Results/Anticipated Results: Among 66 patients in the study, the average age at NEPC diagnosis was 67.5 years. There were no significant differences between the age at diagnosis of de novo and treatment emergent NEPC (t-NEPC). t-NEPC made up 77.3% of the cohort. Median follow-up was 46.5 months (IQR 28–120). The most common alteration was TP53. RB1 alterations were associated with significantly shorter OS compared to patients without RB1 alterations (mOS Not Reached (NR) vs 13.8 months; p = 0.0056). Similarly, patients with high TMB had worse overall survival (mOS NR vs 14.9 months; p = 0.077). We did not observe worse OS in patients with alterations in TP53 or PTEN. RB1 alteration and high TMB were the strongest predictors of worse survival. Discussion/Significance of Impact: RB1 alterations and high TMB predict poor survival in patients with NEPC, highlighting potential biomarkers for risk stratification. TP53 and PTEN did not significantly affect OS. Early genomic profiling and targeted management of actionable alterations such as BRCA and ATM may improve survival and inform future translational studies.
Tabiim et al. (Wed,) studied this question.