Immune Activation by DNA Damage Predicts Response to Chemotherapy and Survival in Oesophageal Adenocarcinoma

Objective Current strategies to guide selection of neo-adjuvant therapy in oesophageal adenocarcinoma (OAC) are inadequate. We assessed the ability of a DNA Damage Immune Response (DDIR) assay to predict response following neo-adjuvant chemotherapy in OAC. Design Transcriptional profiling of 273 formalin fixed paraffin embedded (FFPE) pre-chemotherapy endoscopic OAC biopsies was performed. All patients were treated with platinum-based neo-adjuvant chemotherapy and resection between 2003 and 2014 at four centres in the OCCAMS 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 (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 0.38-0.98; p=0.042) and OS (HR 0.52; 95% CI 0.31-0.88; 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 (intra-tumoural p< 0.001; stromal p= 0.026) as well as PD-L1 expression (intra-tumoural p= 0.047; stromal p= 0.025). Conclusion The DDIR assay is strongly predictive of benefit from DNA-damaging neo-adjuvant chemotherapy followed by surgical resection and is associated with a pro-inflammatory micro-environment in OAC.