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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.

SUBMITTER: Turkington RC

PROVIDER: S-EPMC6839732 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Turkington Richard C RC Knight Laura A LA Blayney Jaine K JK Secrier Maria M Douglas Rosalie R Parkes Eileen E EE Sutton Eilis K EK Stevenson Leanne L McManus Damian D Halliday Sophia S McCavigan Andrena M AM Logan Gemma E GE Walker Steven M SM Steele Christopher J CJ Perner Juliane J Bornschein Jan J MacRae Shona S Miremadi Ahmad A McCarron Eamon E McQuaid Stephen S Arthur Kenneth K James Jacqueline A JA Eatock Martin M MM O'Neill Robert R Noble Fergus F Underwood Timothy J TJ Harkin D Paul DP Salto-Tellez Manuel M Fitzgerald Rebecca C RC Kennedy Richard D RD

Gut 20190309 11

<h4>Objective</h4>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.<h4>Design</h4>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 ...[more]

PMID: 30852560

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Dataset Information

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

Publications

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

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