Patient-derived organoids from metastatic colorectal cancer mirror tumor heterogeneity and predict patient survival and drug sensitivity.

This study reports the pharmacogenomic analysis of tumor heterogeneity in a living biobank of 213 organoids derived from liver metastases of 102 patients with metastatic colorectal cancer. Successful organoid establishment reflects poorer chemosensitivity and patient survival. Molecular fidelity is confirmed in tumor-organoid pairs, and multi-modal phenotypes are defined based on organoid morphology. Cystic morphology associates with intestinal stem cell markers and greater drug sensitivity, while solid morphology is linked to markers of plasticity and aggressiveness. The potential to identify treatments less affected by tumor heterogeneity is supported by multi-lesion analyses in 65 patients. Clinical translation is illustrated in two prospective cases of pharmacogenomics-guided treatment, including successful chemotherapy rechallenge and targeted therapy resistance in cancers with low and high heterogeneity. All pharmacogenomic data are openly available as a functional oncology resource to support interpretation of ex vivo drug sensitivities into clinical "actionability."