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Life sciences · Journal article
The Prostate · October 11, 2026
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ABSTRACT Background Chronic exposure to androgen receptor (AR)‐targeted therapies can drive lineage plasticity, leading to treatment resistance and neuroendocrine prostate cancer (NEPC), characterized by loss of AR expression and acquisition of neuroendocrine (NE) markers including synaptophysin (SYP). We evaluated concordance between circulating tumor cell (CTC) AR and SYP expression patterns and evidence of NE differentiation defined by clinical, pathologic, and genomic features. Methods CTCs from patients with metastatic castration‐resistant prostate cancer (mCRPC) were analyzed using the RareCyte platform with quantitative immunofluorescence imaging for SYP and AR. In patients with ≥ 5 CTCs, associations of CTC phenotype with PSA at collection and overall survival (OS) were assessed using the Wilcoxon rank‐sum test, Fisher's exact test, and Kaplan–Meier analysis. Patients were retrospectively classified as AR‐positive adenocarcinoma or NE‐differentiated based on clinical, pathologic, and genomic data. Results The AR/SYP CTC assay was analytically validated using cell‐line spike‐in models, achieving > 90% accuracy for both biomarkers. Of 52 patients with mCRPC, 27 had ≥ 5 evaluable CTCs and were included in the primary CTC phenotype analyses. The NE‐differentiated cohort had a higher fraction of SYP‐positive CTCs (median 28.6% vs 0.0%, p = 0.0084), whereas the AR‐positive adenocarcinoma cohort had a higher fraction of AR‐positive CTCs (median 96.7% vs 0.0%, p = 0.0004). Classification based on high AR or SYP expression (≥ 80% of CTCs positive) significantly distinguished cohorts and was associated with tissue histology ( p = 0.0048). PSA at CTC collection was lower in the NE‐differentiated cohort (median 3.83 vs 486.89 ng/mL; 95% CI: −1016 to −190.9). OS did not significantly differ between groups. Conclusion SYP and AR CTC expression showed strong concordance with tissue histology and clinical features of NE differentiation and AR‐positive adenocarcinoma. These findings support the feasibility of CTC immunophenotyping to characterize lineage‐associated phenotypes including SYP‐expressing NE differentiation in mCRPC. Prospective validation in larger cohorts with matched tissue biopsies is needed to define the clinical utility of this approach.