Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

Abstract

Background
An improved understanding of which gastroesophageal adenocarcinoma (GOA) patients respond to both chemotherapy and immune checkpoint inhibitors (ICI) is needed. We investigated the predictive role and underlying biology of a 44-gene DNA damage immune response (DDIR) signature in patients with advanced GOA.

Materials and methods
Transcriptional profiling was carried out on pretreatment tissue from 252 GOA patients treated with platinum-based chemotherapy (three dose levels) within the randomized phase III GO2 trial. Cross-validation was carried out in two independent GOA cohorts with transcriptional profiling, immune cell immunohistochemistry and epidermal growth factor receptor (EGFR) fluorescent in situ hybridization (FISH) (n = 430).

Results
In the GO2 trial, DDIR-positive tumours had a greater radiological response (51.7% versus 28.5%, P = 0.022) and improved overall survival in a dose-dependent manner (P = 0.028). DDIR positivity was associated with a pretreatment inflamed tumour microenvironment (TME) and increased expression of biomarkers associated with ICI response such as CD274 (programmed death-ligand 1, PD-L1) and a microsatellite instability RNA signature. Consensus pathway analysis identified EGFR as a potential key determinant of the DDIR signature. EGFR amplification was associated with DDIR negativity and an immune cold TME.

Conclusions
Our results indicate the importance of the GOA TME in chemotherapy response, its relationship to DNA damage repair and EGFR as a targetable driver of an immune cold TME. Chemotherapy-sensitive inflamed GOAs could benefit from ICI delivered in combination with standard chemotherapy. Combining EGFR inhibitors and ICIs warrants further investigation in patients with EGFR-amplified tumours.

People
Baxter, Mark
Author

Mactier, Karen and Baxter, Mark and Peters, Adam and Fair, Katherine and Hannington, Laura and Robertson, James and Wood, Georgina and Sarwar, Asma and Bishr, Mai and Webb, Rebekah and Al-Zubaidi, Mohammed and Eastlake, Leonie and Lankester, Kate and McInerney, Samuel and Creedon, Helen and Stillie, Alison and Purshouse, Karin (2024) TOURISM study (Treatment Outcomes in UteRIne SarcoMa): a 10-year retrospective evaluation of practice in the UK. BMJ Open, 14 (12): e094838. ISSN 2044-6055

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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Spender, Lindsay
Author

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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Cairns, David
Author

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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Walsh, S.
Author

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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Oparka, R.
Author

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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Porter, R. J.
Author

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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Bray, S.
Author

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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Skinner, G.
Author

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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King, S.
Author

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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Turbitt, J.
Author

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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Collinson, D.
Author

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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Miedzybrodzka, Z. H.
Author

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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Jellema, G.
Author

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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Logan, G.
Author

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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Kennedy, Richard
Author

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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Turkington, Richard
Author

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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McLean, Mairi H.
Author

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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Swinson, D.
Author

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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Grabsch, H. I.
Author

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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lord, simon
Author

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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Seymour, Matthew
Author

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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Hall, P. S.
Author

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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Petty, R. D.
Author

Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D. (2024) An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma. ESMO Open, 9 (5): 103450. ISSN 2059-7029

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Title:
An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma
Creators:
Baxter, Mark and Spender, Lindsay and Cairns, David and Walsh, S. and Oparka, R. and Porter, R. J. and Bray, S. and Skinner, G. and King, S. and Turbitt, J. and Collinson, D. and Miedzybrodzka, Z. H. and Jellema, G. and Logan, G. and Kennedy, Richard and Turkington, Richard and McLean, Mairi H. and Swinson, D. and Grabsch, H. I. and lord, simon and Seymour, Matthew and Hall, P. S. and Petty, R. D.
Identification Number:
10.1016/j.esmoop.2024.103450
Date:
May 2024
Divisions:
College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Publisher:
Elsevier
Additional Information:
This work was supported by a Cancer Research UK Biomarker grant [grant number C22029/A29637] and the Scottish Chief Scientist Office [grant number CAF/20/01].
Library
URI:
https://pub.demo35.eprints-hosting.org/id/eprint/273
Item Type:
Article
Depositing User:
Unnamed user with email ejo1f20@soton.ac.uk
Date Deposited:
11 Jun 2025 16:36
Revision:
12
Last Modified:
12 Jun 2025 11:22
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