PT  - JOURNAL ARTICLE
AU  - Richard C Turkington
AU  - Laura A Knight
AU  - Jaine K Blayney
AU  - Maria Secrier
AU  - Rosalie Douglas
AU  - Eileen E Parkes
AU  - Eilis K Sutton
AU  - Leanne Stevenson
AU  - Damian McManus
AU  - Sophia Halliday
AU  - Andrena M McCavigan
AU  - Gemma E Logan
AU  - Steven M Walker
AU  - Christopher J Steele
AU  - Juliane Perner
AU  - Jan Bornschein
AU  - Shona MacRae
AU  - Ahmad Miremadi
AU  - Eamon McCarron
AU  - Stephen McQuaid
AU  - Kenneth Arthur
AU  - Jacqueline A James
AU  - Martin M Eatock
AU  - Robert O’Neill
AU  - Fergus Noble
AU  - Timothy J Underwood
AU  - D Paul Harkin
AU  - Manuel Salto-Tellez
AU  - Rebecca C Fitzgerald
AU  - Richard D Kennedy
ED  - ,
TI  - Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma
AID  - 10.1136/gutjnl-2018-317624
DP  - 2019 Nov 01
TA  - Gut
PG  - 1918--1927
VI  - 68
IP  - 11
4099  - http://gut.bmj.com/content/68/11/1918.short
4100  - http://gut.bmj.com/content/68/11/1918.full
SO  - Gut2019 Nov 01; 68
AB  - 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.