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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.

Original publication

DOI

10.1136/gutjnl-2018-317624

Type

Journal article

Journal

Gut

Publication Date

11/2019

Volume

68

Pages

1918 - 1927

Addresses

Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.

Keywords

Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Study Group, CD8-Positive T-Lymphocytes, Humans, Adenocarcinoma, Esophageal Neoplasms, DNA Damage, Antineoplastic Agents, Disease-Free Survival, Treatment Outcome, Chemotherapy, Adjuvant, Neoadjuvant Therapy, Esophagectomy, Survival Rate, Predictive Value of Tests, Aged, Middle Aged, Female, Male, B7-H1 Antigen