AUTHOR=Kyrochristos Ioannis D. , Glantzounis Georgios K. , Goussia Anna , Eliades Alexia , Achilleos Achilleas , Tsangaras Kyriakos , Hadjidemetriou Irene , Elpidorou Marilena , Ioannides Marios , Koumbaris George , Mitsis Michail , Patsalis Philippos C. , Roukos Dimitrios 

TITLE=Proof-of-Concept Pilot Study on Comprehensive Spatiotemporal Intra-Patient Heterogeneity for Colorectal Cancer With Liver Metastasis

JOURNAL=Frontiers in Oncology

VOLUME=Volume 12 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.855463

DOI=10.3389/fonc.2022.855463

ISSN=2234-943X

ABSTRACT=Introduction: The 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. 
Objective: We 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.
Methods: A total of 122 multi-regional tumor and perioperative liquid biopsies from 18 patients were analyzed via targeted next-generation sequencing (NGS).
Results: The 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.
Conclusion: Our 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 IPH-driven matched therapy.