Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma.

Abstract:

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.

journal_name

Gut

journal_title

Gut

authors

Turkington RC,Knight LA,Blayney JK,Secrier M,Douglas R,Parkes EE,Sutton EK,Stevenson L,McManus D,Halliday S,McCavigan AM,Logan GE,Walker SM,Steele CJ,Perner J,Bornschein J,MacRae S,Miremadi A,McCarron E,McQuaid S,

doi

10.1136/gutjnl-2018-317624

subject

Has Abstract

pub_date

2019-11-01 00:00:00

pages

1918-1927

issue

11

eissn

0017-5749

issn

1468-3288

pii

gutjnl-2018-317624

journal_volume

68

pub_type

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