Journal
GUT
Volume 68, Issue 11, Pages 1918-1927Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2018-317624
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Funding
- Belfast Health and Social Care Trust Gastrointestinal Cancer Research Fund
- Almac Diagnostics
- Cancer Research UK
- HSC Research and Development Division of the Public Health Agency in Northern Ireland
- National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre
- Invest Northern Ireland
- Medical Research Council
- Cancer Research UK
- Versus Arthritis [20406] Funding Source: researchfish
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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.
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