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

Cancer Cell. 2018 Jul 9;34(1):148-162.e7. doi: 10.1016/j.ccell.2018.06.004.

Abstract

Targeting HER2 is effective in 24% of ERBB2 amplified metastatic colorectal cancer; however, secondary resistance occurs in most of the cases. We studied the evolution of individual metastases during treatment to discover spatially resolved determinants of resistance. Circulating tumor DNA (ctDNA) analysis identified alterations associated with resistance in the majority of refractory patients. ctDNA profiles and lesion-specific radiographic reports revealed organ- or metastasis-private evolutionary patterns. When radiologic assessments documented progressive disease in target lesions, response to HER2 blockade was retained in other metastases. Genomic and functional analyses on samples and cell models from eight metastases of a patient co-recruited to a postmortem study unveiled lesion-specific evolutionary trees and pharmacologic vulnerabilities. Lesion size and contribution of distinct metastases to plasma ctDNA were correlated.

Keywords: HER2 amplification; clonal evolution; colorectal cancer; ctDNA; lapatinib; liquid biopsy; rapid autopsy; resistance; targeted therapy; trastuzumab.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / diagnostic imaging
  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / genetics
  • Adenocarcinoma / secondary
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Clinical Decision-Making
  • Colorectal Neoplasms / diagnostic imaging
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • DNA Mutational Analysis
  • Disease Progression
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Gene Amplification
  • Humans
  • Italy
  • Lapatinib / administration & dosage*
  • Lapatinib / adverse effects
  • Liquid Biopsy
  • Liver Neoplasms / diagnostic imaging
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / secondary
  • Magnetic Resonance Imaging
  • Male
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • Predictive Value of Tests
  • Progression-Free Survival
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / adverse effects
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / genetics
  • Risk Factors
  • Signal Transduction / drug effects
  • Time Factors
  • Tomography, X-Ray Computed*
  • Trastuzumab / administration & dosage*
  • Trastuzumab / adverse effects
  • Treatment Outcome
  • Tumor Cells, Cultured
  • ras Proteins / genetics

Substances

  • Protein Kinase Inhibitors
  • Lapatinib
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • ras Proteins
  • Trastuzumab