EGFR amplification and outcome in a randomised phase III trial of chemotherapy alone or chemotherapy plus panitumumab for advanced gastro-oesophageal cancers

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Elizabeth C. Smyth - , University of Cambridge, Royal Marsden NHS Foundation Trust (Author)
  • Georgios Vlachogiannis - , Birkbeck University of London (Author)
  • Somaieh Hedayat - , Birkbeck University of London (Author)
  • Alice Harbery - , Birkbeck University of London (Author)
  • Sanna Hulkki-Wilson - , Birkbeck University of London (Author)
  • Massimiliano Salati - , Birkbeck University of London (Author)
  • Kyriakos Kouvelakis - , Royal Marsden NHS Foundation Trust (Author)
  • Javier Fernandez-Mateos - , Birkbeck University of London (Author)
  • George D. Cresswell - , Birkbeck University of London (Author)
  • Elisa Fontana - , Birkbeck University of London (Author)
  • Therese Seidlitz - , Department of Visceral, Thoracic and Vascular Surgery, Dresden University of Technology (Author)
  • Clare Peckitt - , Royal Marsden NHS Foundation Trust (Author)
  • Jens C. Hahne - , Birkbeck University of London (Author)
  • Andrea Lampis - , Birkbeck University of London (Author)
  • Ruwaida Begum - , Royal Marsden NHS Foundation Trust (Author)
  • David Watkins - , Royal Marsden NHS Foundation Trust (Author)
  • Sheela Rao - , Royal Marsden NHS Foundation Trust (Author)
  • Naureen Starling - , Royal Marsden NHS Foundation Trust (Author)
  • Tom Waddell - , Royal Marsden NHS Foundation Trust, The Christie NHS Foundation Trust (Author)
  • Alicia Okines - , Royal Marsden NHS Foundation Trust (Author)
  • Tom Crosby - , Velindre Cancer Centre (Author)
  • Was Mansoor - , The Christie NHS Foundation Trust (Author)
  • Jonathan Wadsley - , Canc Clin Trials Ctr (Author)
  • Gary Middleton - , University of Birmingham (Author)
  • Matteo Fassan - , University of Padua (Author)
  • Andrew Wotherspoon - , Royal Marsden NHS Foundation Trust (Author)
  • Chiara Braconi - , Royal Marsden NHS Foundation Trust, Birkbeck University of London, University of Glasgow (Author)
  • Ian Chau - , Royal Marsden NHS Foundation Trust (Author)
  • Igor Vivanco - , Birkbeck University of London (Author)
  • Andrea Sottoriva - , Birkbeck University of London (Author)
  • Daniel E. Stange - , German Center for Neurodegenerative Diseases, Dresden site (Partner: DZNE of the Helmholtz Association), Department of Visceral, Thoracic and Vascular Surgery, Dresden University of Technology (Author)
  • David Cunningham - , Royal Marsden NHS Foundation Trust (Author)
  • Nicola Valeri - , Royal Marsden NHS Foundation Trust, Birkbeck University of London (Author)

Abstract

Objective Epidermal growth factor receptor (EGFR) inhibition may be effective in biomarker-selected populations of advanced gastro-oesophageal adenocarcinoma (aGEA) patients. Here, we tested the association between outcome and EGFR copy number (CN) in pretreatment tissue and plasma cell-free DNA (cfDNA) of patients enrolled in a randomised first-line phase III clinical trial of chemotherapy or chemotherapy plus the anti-EGFR monoclonal antibody panitumumab in aGEA (NCT00824785).Design EGFR CN by either fluorescence in situ hybridisation (n=114) or digital-droplet PCR in tissues (n=250) and plasma cfDNAs (n=354) was available for 474 (86%) patients in the intention-to-treat (ITT) population. Tissue and plasma low-pass whole-genome sequencing was used to screen for coamplifications in receptor tyrosine kinases. Interaction between chemotherapy and EGFR inhibitors was modelled in patient-derived organoids (PDOs) from aGEA patients.Results EGFR amplification in cfDNA correlated with poor survival in the ITT population and similar trends were observed when the analysis was conducted in tissue and plasma by treatment arm. EGFR inhibition in combination with chemotherapy did not correlate with improved survival, even in patients with significant EGFR CN gains. Addition of anti-EGFR inhibitors to the chemotherapy agent epirubicin in PDOs, resulted in a paradoxical increase in viability and accelerated progression through the cell cycle, associated with p21 and cyclin B1 downregulation and cyclin E1 upregulation, selectively in organoids from EGFR-amplified aGEA.Conclusion EGFR CN can be accurately measured in tissue and liquid biopsies and may be used for the selection of aGEA patients. EGFR inhibitors may antagonise the antitumour effect of anthracyclines with important implications for the design of future combinatorial trials.

Details

Original languageEnglish
Pages (from-to)1632-1641
Number of pages10
JournalGut
Volume70
Issue number9
Publication statusPublished - Sept 2021
Peer-reviewedYes

External IDs

PubMed 33199443
Scopus 85096445555
ORCID /0000-0001-7367-5525/work/151437325

Keywords

Keywords

  • Colorectal-cancer, Gastric-cancer, Open-label, Oxaliplatin, Cetuximab, Resistance, Biomarker, Her2, Heterogeneity, Capecitabine