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

Richard Turkington*, Laura Knight, Jaine Blayney, Maria Secrier, Rosalie Douglas, Eileen Parkes, Eilis Sutton, Leanne Stevenson, Damian McManus, Sophia Halliday, Andrena McCavigan, Gemma Logan, Steven Walker, Christopher Steele, Juliane Perner, Jan Bornscein, Shona MacRae, Ahmad Miremadi, Eamon mccarron, Stephen McQuaidKenneth Arthur, Jacqueline James, Martin Eatock, Robert O'Neill, Fergus Noble, Timothy Underwood, Denis Harkin, Manuel Salto-Tellez, Rebecca C Fitzgerald, Richard Kennedy

*Corresponding author for this work

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Abstract

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.
Original languageEnglish
Number of pages10
JournalGut
DOIs
Publication statusPublished - 09 Mar 2019

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Keywords

  • oesophageal cancer
  • biomarker
  • predicitve

Cite this

Turkington, R., Knight, L., Blayney, J., Secrier, M., Douglas, R., Parkes, E., Sutton, E., Stevenson, L., McManus, D., Halliday, S., McCavigan, A., Logan, G., Walker, S., Steele, C., Perner, J., Bornscein, J., MacRae, S., Miremadi, A., mccarron, E., ... Kennedy, R. (2019). Immune Activation by DNA Damage Predicts Response to Chemotherapy and Survival in Oesophageal Adenocarcinoma. Gut. https://doi.org/10.1136/gutjnl-2018-317624