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

Ioannis D Kyrochristos1,2, Georgios K Glantzounis3, Anna Goussia4

  • 1Centre for Biosystems and Genome Network Medicine, Ioannina University, Ioannina, Greece.

Frontiers in Oncology
|April 11, 2022
PubMed
Summary

Intra-patient heterogeneity (IPH) in colorectal cancer (CRC) liver metastasis (LM) reveals new mutations, guiding targeted therapy. Understanding IPH is crucial for overcoming drug resistance and improving patient outcomes.

Keywords:
actionable mutationscirculating variabilitycomprehensive intra-patient heterogeneityintratumor heterogeneitynext-generation sequencingprecision cancer medicine

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Area of Science:

  • Oncology
  • Genomics
  • Translational Research

Background:

  • Colorectal cancer (CRC) with liver metastasis (LM) exhibits high drug resistance and relapse rates after multi-modal treatment.
  • The underlying mechanisms, particularly intra-patient heterogeneity (IPH), are not well understood.

Purpose of the Study:

  • To evaluate the translational implications of IPH, including primary and metastatic intratumor heterogeneity (ITH) and circulating tumor DNA (ctDNA) variability.
  • To investigate the role of spatiotemporal tumor evolution in CRC and LM.

Main Methods:

  • Targeted next-generation sequencing (NGS) of 122 multi-regional tumor and perioperative liquid biopsies from 18 patients.
  • Analysis of primary CRC, matched LM, and ctDNA for ITH and novel mutations.

Main Results:

  • ITH was present in 53% of primary CRC and 56% of LM.
  • 35% of patients showed de novo mutations in LM, and 25% had de novo cfDNA mutations undetectable in primary tumors or metastases.
  • All 17 patients with driver alterations had mutations targetable by molecularly targeted drugs.

Conclusions:

  • IPH analysis, combining ITH and ctDNA, shows potential clinical superiority in CRC with LM.
  • This proof-of-concept study supports precision oncology trials to assess IPH-driven matched therapy's clinical utility.