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IntroductionThe mechanisms underlying high drug resistance and relapse rates after multi-modal treatment in patients with colorectal cancer (CRC) and liver metastasis (LM) remain poorly understood.ObjectiveWe evaluate the potential translational implications of intra-patient heterogeneity (IPH) comprising primary and matched metastatic intratumor heterogeneity (ITH) coupled with circulating tumor DNA (ctDNA) variability.MethodsA total of 122 multi-regional tumor and perioperative liquid biopsies from 18 patients were analyzed via targeted next-generation sequencing (NGS).ResultsThe proportion of patients with ITH were 53% and 56% in primary CRC and LM respectively, while 35% of patients harbored de novo mutations in LM indicating spatiotemporal tumor evolution and the necessity of multiregional analysis. Among the 56% of patients with alterations in liquid biopsies, de novo mutations in cfDNA were identified in 25% of patients, which were undetectable in both CRC and LM. All 17 patients with driver alterations harbored mutations targetable by molecularly targeted drugs, either approved or currently under evaluation.ConclusionOur proof-of-concept prospective study provides initial evidence on potential clinical superiority of IPH and warrants the conduction of precision oncology trials to evaluate the clinical utility of I PH-driven matched therapy.