Pancreatic cancer patient-derived organoids capture therapy response and tumor evolution

Abstract

Patient-derived organoids (PDOs) reflect parental tumor features and may represent promising avatars for prognosticating drug response. Here, we recruited 169 patients with pancreatic cancer (PC) and established a living biobank including 83 pharmacotyped PDOs isolated from primary and metastatic, treatment-naive and pretreated PCs. In a core facility setting, the pharmacotyping success rate was 61.5%, with an unmet turnaround time of 32 days. Forty-six patients who underwent a total of 94 therapeutic lines were analyzed, resulting in a pharmacotyping-patient response matching rate of 73.4%. Sensitivity, specificity, positive and negative predictive values were 85.0%, 64.8%, 64.2%, and 85.4%, respectively. Tracing clonal evolution in longitudinal biopsies uncovered therapy-induced genetic alterations and single-nucleus multiomics identified transcriptomic and epigenetic changes associated with abnormal FGF signaling during treatment in one particular tracked study case. Our findings highlight the potential of PDOs as robust tools for drug response prediction and patient modeling to advance functional precision medicine.