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 McQuaid; Kenneth Arthur; Jacqueline James; Martin Eatock; Robert O'Neill; Fergus Noble; Timothy Underwood; Denis Harkin; Manuel Salto-Tellez; Rebecca C Fitzgerald; Richard Kennedy

doi:10.1136/gutjnl-2018-317624

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

Research output: Contribution to journal › Article › peer-review

19 Citations (Scopus)

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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.

Original language	English
Pages (from-to)	1918-1927
Number of pages	10
Journal	Gut
Volume	68
Issue number	11
Early online date	09 Mar 2019
DOIs	https://doi.org/10.1136/gutjnl-2018-317624
Publication status	Early online date - 09 Mar 2019

Bibliographical note

Keywords

Adenocarcinoma/immunology
Aged
Antineoplastic Agents/therapeutic use
B7-H1 Antigen
CD8-Positive T-Lymphocytes
Chemotherapy, Adjuvant
DNA Damage/immunology
Disease-Free Survival
Esophageal Neoplasms/immunology
Esophagectomy
Female
Humans
Male
Middle Aged
Neoadjuvant Therapy
Predictive Value of Tests
Survival Rate
Treatment Outcome

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1136/gutjnl-2018-317624Licence: CC BY

Immune Activation by DNA Damage Predicts Response to Chemotherapy and Survival in Oesophageal Adenocarcinoma
Copyright 2019 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 1.14 MBLicence: CC BY

UTV- Oesophageal Cancer Interview
Richard Turkington
17/04/2019
1 item of Media coverage
Press/Media: Expert Comment
BBC NI- Oesophageal Cancer Interview
Richard Turkington
17/04/2019
1 item of Media coverage
Press/Media: Expert Comment

Identification of novel therapeutic strategies for immune-active oesophageal adenocarcinoma
Sutton, É. (Author), Turkington, R. (Supervisor) & Kennedy, R. (Supervisor), Jul 2023
Student thesis: Doctoral Thesis › Doctor of Philosophy

File
Identification of targetable mediators of resistance to chemotherapy in oesophageal adenocarcinoma
Douglas, R. (Author), Turkington, R. (Supervisor) & Kennedy, R. (Supervisor), Jul 2021
Student thesis: Doctoral Thesis › Doctor of Philosophy

File
Temporal analysis of clinico-pathological variables and biomarkers in cancer
Halliday, S. (Author), Blayney, J. (Supervisor) & Kennedy, R. (Supervisor), Dec 2019
Student thesis: Doctoral Thesis › Doctor of Philosophy

File

Richard Turkington
- R.Turkingtonqub.acuk
- School of Medicine, Dentistry and Biomedical Sciences - Clinical Reader
- Patrick G Johnston Centre for Cancer Research
Person: Academic

19 Citations
1 Meeting abstract
1 Article

Author’s Response: The unified definition of relapse-free survival should be used for evaluating survival benefit in oesophageal adenocarcinoma
Lavery, A., Blayney, J. & Turkington, R., 30 Jun 2020, (Early online date) In: Gut. 1 p.
Research output: Contribution to journal › Article › peer-review

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226 Downloads (Pure)
Association of a DNA damage response deficiency (DDRD) assay with prognosis in resected esophageal and gastric adenocarcinoma
Turkington, R., Knight, L., Douglas, R., Blayney, J., Stevenson, L., McManus, D., McCavigan, A., Walker, S., Bornschein, J., McRae, S., Noble, F., Underwood, T., O'Neill, R., McQuaid, S., Arthur, K., James, J., Eatock, M., Harkin, D., Fitzgerald, R. C. & Kennedy, R., 01 May 2017, In: Journal of Clinical Oncology : official journal of the American Society of Clinical Oncology. 35, 15_suppl, p. 4026-4026 1 p., 4026.
Research output: Contribution to journal › Meeting abstract › peer-review

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, 68(11), 1918-1927. Advance online publication. https://doi.org/10.1136/gutjnl-2018-317624

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title = "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.",

keywords = "Adenocarcinoma/immunology, Aged, Antineoplastic Agents/therapeutic use, B7-H1 Antigen, CD8-Positive T-Lymphocytes, Chemotherapy, Adjuvant, DNA Damage/immunology, Disease-Free Survival, Esophageal Neoplasms/immunology, Esophagectomy, Female, Humans, Male, Middle Aged, Neoadjuvant Therapy, Predictive Value of Tests, Survival Rate, Treatment Outcome",

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

note = "{\textcopyright} Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",

year = "2019",

month = mar,

day = "9",

doi = "10.1136/gutjnl-2018-317624",

language = "English",

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pages = "1918--1927",

journal = "Gut",

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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, McQuaid, S, Arthur, K, James, J, Eatock, M, O'Neill, R, Noble, F, Underwood, T, Harkin, D, Salto-Tellez, M, Fitzgerald, RC & Kennedy, R 2019, 'Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma', Gut, vol. 68, no. 11, pp. 1918-1927. https://doi.org/10.1136/gutjnl-2018-317624

TY - JOUR

T1 - Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma

AU - Turkington, Richard

AU - Knight, Laura

AU - Blayney, Jaine

AU - Secrier, Maria

AU - Douglas, Rosalie

AU - Parkes, Eileen

AU - Sutton, Eilis

AU - Stevenson, Leanne

AU - McManus, Damian

AU - Halliday, Sophia

AU - McCavigan, Andrena

AU - Logan, Gemma

AU - Walker, Steven

AU - Steele, Christopher

AU - Perner, Juliane

AU - Bornscein, Jan

AU - MacRae, Shona

AU - Miremadi, Ahmad

AU - McCarron, Eamon

AU - McQuaid, Stephen

AU - Arthur, Kenneth

AU - James, Jacqueline

AU - Eatock, Martin

AU - O'Neill, Robert

AU - Noble, Fergus

AU - Underwood, Timothy

AU - Harkin, Denis

AU - Salto-Tellez, Manuel

AU - Fitzgerald, Rebecca C

AU - Kennedy, Richard

PY - 2019/3/9

Y1 - 2019/3/9

N2 - 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.

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.

KW - Adenocarcinoma/immunology

KW - Aged

KW - Antineoplastic Agents/therapeutic use

KW - B7-H1 Antigen

KW - CD8-Positive T-Lymphocytes

KW - Chemotherapy, Adjuvant

KW - DNA Damage/immunology

KW - Disease-Free Survival

KW - Esophageal Neoplasms/immunology

KW - Esophagectomy

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Neoadjuvant Therapy

KW - Predictive Value of Tests

KW - Survival Rate

KW - Treatment Outcome

U2 - 10.1136/gutjnl-2018-317624

DO - 10.1136/gutjnl-2018-317624

M3 - Article

C2 - 30852560

AN - SCOPUS:85062672043

SN - 0017-5749

VL - 68

SP - 1918

EP - 1927

JO - Gut

JF - Gut

IS - 11

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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