Patient-derived organoids predict treatment response in metastatic colorectal cancer

Abstract

PURPOSE: Accurately predicting treatment response in metastatic colorectal cancer (mCRC) is critical to avoid unnecessary toxicity and improve patient outcomes. Patient-derived organoids (PDO) are promising models, but larger prospective studies are needed to confirm their predictive value. EXPERIMENTAL DESIGN: Patients with mCRC underwent a metastatic biopsy for PDO establishment, before starting new systemic treatment. Predictors of PDO establishment were identified. PDOs were incubated with a seven-drug panel, including the patient's treatment, to determine drug sensitivity as measured by CyQUANT cell viability [area under the nonfitted "curve" of the raw viability or growth rate inhibition values (AUC and GRAUC) and concentration that gives half-maximal viability or GR inhibition (IC50 and GR50)]. Patient response was measured by size change of biopsied and all target lesions. The diagnostic performance was evaluated by positive predictive value, negative predictive value, and area under the ROC curve. Additionally, the association between PDO response and survival was assessed. RESULTS: A total of 232 patients were included, and 205 biopsies were obtained. PDO establishment success increased from 22% to 75%, yielding 52% overall. Male sex, increased lactate dehydrogenase, biopsy in academic hospitals, optimized culture conditions, and experience were related to PDO establishment success. In this interim analysis, focused on oxaliplatin-based doublet chemotherapy, 42 PDOs were screened. PDO drug sensitivity significantly correlated with the response of the biopsied lesion (R = 0.41-0.49, P < 0.011) and all target lesions (R = 0.54-0.60, P < 0.001) for all treatments combined. The 5-fluorouracil and oxaliplatin PDO screens demonstrated high predictive accuracy (positive predictive value: 0.78; negative predictive value: 0.80; area under the ROC curve: 0.78-0.88) and were associated with progression-free survival and overall survival (P = 0.016 and 0.049). CONCLUSIONS: We identified predictors for successful mCRC PDO establishment and validated that PDOs can accurately predict patient outcomes during systemic treatment, specifically with 5-fluorouracil and oxaliplatin.