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Radiologic and Genomic Evolution of Individual Metastases during HER2 Blockade in Colorectal Cancer

Giulia Siravegna1, Luca Lazzari2, Giovanni Crisafulli3

  • 1Candiolo Cancer Institute-FPO, IRCCS, Candiolo, TO, Italy.

Cancer Cell
|July 11, 2018
PubMed

Insights

Targeting HER2 in metastatic colorectal cancer shows limited efficacy due to resistance. Studying individual metastases revealed distinct evolutionary patterns and identified circulating tumor DNA (ctDNA) as a key indicator of resistance.

Area of Science:

  • Oncology
  • Genomics
  • Cancer Metastasis Research

Background:

  • HER2-targeted therapy is effective in a subset of ERBB2-amplified metastatic colorectal cancer (mCRC).
  • Secondary resistance to HER2 blockade limits long-term patient benefit.
  • Understanding resistance mechanisms at a spatially resolved level is crucial for improving treatment strategies.

Purpose of the Study:

  • To investigate the evolution of individual metastases during HER2-targeted therapy in mCRC.
  • To identify determinants of spatial resistance to HER2 blockade.
  • To correlate circulating tumor DNA (ctDNA) profiles with metastatic evolution and treatment response.

Main Methods:

  • Analysis of circulating tumor DNA (ctDNA) from refractory patients.
  • Correlation of ctDNA profiles with lesion-specific radiographic reports.
  • Genomic and functional analyses of patient-derived metastases and cell models.
  • Postmortem study of eight metastases from a single patient.

Main Results:

  • ctDNA analysis identified resistance-associated alterations in most refractory patients.
  • Metastases exhibited organ- or metastasis-private evolutionary patterns.
  • HER2 blockade response was retained in some metastases despite progression in others.
  • Lesion-specific evolutionary trees and vulnerabilities were uncovered.
  • Metastasis size and ctDNA contribution to plasma were correlated.

Conclusions:

  • Metastatic colorectal cancer exhibits heterogeneous evolution during HER2-targeted therapy.
  • Spatially resolved analysis of metastases and ctDNA provides insights into resistance mechanisms.
  • Individual metastases can display distinct responses and evolutionary trajectories.
  • Understanding these patterns may guide the development of more effective therapeutic strategies.
Keywords:
HER2 amplificationclonal evolutioncolorectal cancerctDNAlapatinibliquid biopsyrapid autopsyresistancetargeted therapytrastuzumab

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