Clinical investigation of neuroendocrine differentiation in prostate cancer. A study focused on neuroendocrine tumor markers

Abstract Background: Compared to prostate adenocarcinoma, neuroendocrine prostate cancer (NEPC) is characterized by aggressive tumor biology and a limited prognosis. Several studies have focused on tumor markers to assess neuroendocrine differentiation and treatment outcomes. However, few studies have investigated changes in tumor markers throughout the clinical course. This study was an observational analysis of neuroendocrine differentiation, survival rates, and temporal changes in prostate cancer. Methods: A total of 193 prostate cancer cases were included in this study. We tested circulating neuroendocrine tumor markers, including neuron specific enolase (NSE) and pro-gastrin releasing peptide (pro-GRP), and evaluated the positive rates of these markers. In relation to castration-resistant prostate cancer (CRPC), we assessed the changes in the positive rates of neuroendocrine tumor markers over time. Results: The positive rate of circulating neuroendocrine markers (defined as at least one marker exceeding the normal limit) was 23.5% in hormone sensitive prostate cancer (HSPC) and 59.5% in CRPC. In the context of CRPC, pro-GRP was significantly associated with prognosis. The median overall survival (OS) for patients with normal pro-GRP levels was 78 months (95% CI: 55-112), while for those with positive pro-GRP levels, it was 36.5 months (95% CI: 9-89) (p=0.0216). The initial positive rate (defined as at least one of NSE or pro-GRP being positive) at the beginning of this study was 61.5% overall; however, by the end of the follow-up period, approximately four years later, this rate had increased to 92.3%. Conclusions: Neuroendocrine tumor markers are significantly elevated in CRPC and correlated with survival outcomes. The positivity rate of these tumor markers increased during CRPC treatment, with most cases ultimately testing positive. This suggests that treatment-emergent neuroendocrine differentiation may occur more frequently than previously anticipated. These findings should be considered in real-world clinical practice.