Personalized prediction of chemotherapy efficacy in osteosarcoma through patient-derived organoids: correlation with survival and tumor proliferation potential.
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BACKGROUND: Neoadjuvant chemotherapy (NAT) is the standard treatment for osteosarcoma (OS), but patient responses vary, and conventional imaging or pathology offers limited predictive accuracy. Patient-derived organoids (PDOs) are promising models for assessing drug sensitivity and tumor viability ex vivo. This study evaluated the potential of PDO-based drug sensitivity testing and organoid formation potential (OFP) to predict therapeutic outcomes in OS. METHODS: Tumor samples from OS patients collected before and after NAT were cultured as 3D PDOs. Chemosensitivity to first-line agents was quantified via a cell inhibition weighted score (CIWS), whereas OFP was used to reflect residual tumor viability. Clinical response was assessed via RECIST 1.1 and, for the primary analysis, dichotomized as responder (CR+PR+SD) versus nonresponder (PD); survival (OS/DFS) was tracked for up to 5 years. Correlations between PDO metrics and clinical outcomes were analyzed. RESULTS: PDOs were established from 31 samples (18 pre-NAT samples and 13 post-NAT samples), including 8 paired pre/post-NAT samples. CIWS predicted NAT response assessed by RECIST 1.1 with 83.3% accuracy (pre-NAT, 15/18; 95% CI 58.6-96.4) and 5-year DFS with 84.6% accuracy (post-NAT, 11/13; 95% CI 54.6-98.1). With predefined CIWS/OFP cutoffs, Kaplan-Meier analyses showed longer DFS/OS in CIWS-sensitive and OFP-II/III (low growth) groups (P<0.05). CONCLUSIONS: PDOs demonstrated promise as an ex vivo approach to evaluate whether ex vivo chemosensitivity and residual tumor viability measured by PDOs are associated with imaging response and 5-year survival. Their correlation with clinical outcomes highlights the potential of PDO testing to complement existing evaluation methods and to inform individualized treatment strategies.