Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma

Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Study Group

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Objective Current strategies to guide selection of neoadjuvant therapy in oesophageal adenocarcinoma (OAC) are inadequate. We assessed the ability of a DNA damage immune response (DDIR) assay to predict response following neoadjuvant chemotherapy in OAC. Design Transcriptional profiling of 273 formalin-fixed paraffin-embedded prechemotherapy endoscopic OAC biopsies was performed. All patients were treated with platinum-based neoadjuvant chemotherapy and resection between 2003 and 2014 at four centres in the Oesophageal Cancer Clinical and Molecular Stratification consortium. CD8 and programmed death ligand 1 (PD-L1) immunohistochemical staining was assessed in matched resection specimens from 126 cases. Kaplan-Meier and Cox proportional hazards regression analysis were applied according to DDIR status for recurrence-free survival (RFS) and overall survival (OS). Results A total of 66 OAC samples (24%) were DDIR positive with the remaining 207 samples (76%) being DDIR negative. DDIR assay positivity was associated with improved RFS (HR: 0.61; 95% CI 0.38 to 0.98; p=0.042) and OS (HR: 0.52; 95% CI 0.31 to 0.88; p=0.015) following multivariate analysis. DDIR-positive patients had a higher pathological response rate (p=0.033), lower nodal burden (p=0.026) and reduced circumferential margin involvement (p=0.007). No difference in OS was observed according to DDIR status in an independent surgery-alone dataset. DDIR-positive OAC tumours were also associated with the presence of CD8+ lymphocytes (intratumoural: p<0.001; stromal: p=0.026) as well as PD-L1 expression (intratumoural: p=0.047; stromal: p=0.025). Conclusion The DDIR assay is strongly predictive of benefit from DNA-damaging neoadjuvant chemotherapy followed by surgical resection and is associated with a proinflammatory microenvironment in OAC.

Original languageEnglish
Pages (from-to)1918-1927
Number of pages10
JournalGut
Volume68
Issue number11
Early online date9 Mar 2019
DOIs
Publication statusPublished - Nov 2019
Externally publishedYes

Bibliographical note

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.

Keywords

  • Chemotherapy
  • DNA damage
  • Immune response
  • Oesophageal cancer

ASJC Scopus subject areas

  • Gastroenterology

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