Abstract / Summary
Abstract Tumors of uncertain differentiation (TUD) are rare and heterogeneous with poor prognosis. In this study, We investigated the potential clinical utility of patient-derived organoid (PDO) in precision treatment of TUD. Patients whose subsequent treatment decisions guided by PDO drug sensitivity results comprised the PDO-guided cohort, while a contemporaneous cohort treated without PDO guidance served as the control cohort. 12 of 13 (92.3%) PDO-guided patients showed concordant clinical outcomes. PDO-guided cohort had superior median cumulative PFS (18.88 vs. 6.22 months, P = 0.016) and first-line PFS (2.00 vs. 1.77 months, P = 0.046) versus controls. In intra-patient analyses, 4 of 7 evaluable patients achieved an Effective PFS ratio ≥ 1.3, and all evaluable PDO-guided patients had PFS1/DFS ratios > 1.3, whereas ratios were generally < 1.3 in the control cohort. Marked inter-patient heterogeneity in drug responses was observed in PDO drug sensitivity profiling. Doxorubicin plus immune checkpoint inhibitors (ICI) showed higher inhibitory activity. Patients with more prior lines of therapy showed lower maximal PDO inhibition (r = -0.46, P = 0.024). Furthermore, patients with higher PDO inhibitory activity experienced a significantly longer time to the appearance of new lesions (24.00 vs. 8.00, log-rank P = 0.044). These findings support the clinical relevance of PDO-based drug sensitivity profiling for individualized treatment in TUD. PDO profiling may provide a complementary approach to precision treatment in this rare and highly heterogeneous group of malignancies.