@article{febf00d8d2f84cd2b1fb8235438c7a40,
title = "An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma",
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.",
keywords = "DNA damage immune response, epidermal growth factor receptor, gastroesophageal adenocarcinoma, immune checkpoint inhibitors, tumour microenvironment",
author = "Baxter, \{M. A.\} and Spender, \{L. C.\} and D. Cairns and S. Walsh and R. Oparka and Porter, \{R. J.\} and S. Bray and G. Skinner and S. King and J. Turbitt and D. Collinson and Miedzybrodzka, \{Z. H.\} and G. Jellema and G. Logan and Kennedy, \{R. D.\} and Turkington, \{R. C.\} and McLean, \{M. H.\} and D. Swinson and Grabsch, \{H. I.\} and S. Lord and Seymour, \{M. J.\} and Hall, \{P. S.\} and Petty, \{R. D.\}",
note = "Funding Information: The GO2 trial was funded by Cancer Research UK (trial number: CRUK/12/022), ran within the UK National Health Service and was supported by the National Institute for Health Research (NIHR) Clinical Research Network. HIG is supported in part by the National Institute for Health and Care Research (NIHR) Leeds Biomedical Research Centre. Funders had no role in designing, undertaking or reporting the study, and the views expressed in this publication are those of the author(s) and not necessarily those of the funders, NHS or the UK Department of Health and Social Care. The authors would also like to acknowledge the GO2 trial investigators and OCCAMS, a multicentre UK collaboration (Supplementary Materials, available at https://doi.org/10.1016/j.esmoop.2024.103450). OCCAMS was funded by a Programme Grant from Cancer Research UK (RG66287, A15874). OCCAMS2 was funded by a Programme Grant from Cancer Research UK (RG81771/RG84119, A22720/A22131). In addition, we would like to acknowledge the NHS Research Scotland (NRS) biorepositories in Tayside and Grampian. 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]. MAB reported personal fees from Ipsen, BMS and Servier. RDP reported personal fees from Eli Lilly, Bristol Myers Squib, and Servier and grants from AstraZeneca, Roche, Sanofi, Merck Sharp \& Dohme, Five Prime Therapeutics and Jansen outside the submitted work. MJS reported grants from Cancer Research UK during the conduct of the GO2 study. PSH reported grants from Cancer Research UK during the conduct of the study and institutional research funding from Novartis, Pfizer, Eli Lilly, Daiichi-Sankyo and Eisai outside the submitted work. GL and RDK are employees of Almac Diagnostic Services. RT reported personal fees from Eli Lilly, Astellas and Almac Diagnostic Services outside the submitted work. All other authors have declared no conflicts of interest. The GO2 trial (ISRCTN44687907) was conducted in accordance with the Declaration of Helsinki, approved by the UK National Research Ethics Service and overseen by independent Trial Steering and Data Monitoring \& Ethics Committees. Informed consent for the use of tumour specimens for future biomarker investigation was obtained from all subjects involved in the GO2 study. Funding Information: This study was funded by a Cancer Research UK Biomarker grant (C22029/A29637) and the Scottish Chief Scientist Office (CAF/20/01). Funding Information: The authors would also like to acknowledge the GO2 trial investigators and the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS), a multicenter UK collaboration (Supplementary materials). OCCAMS was funded by a Programme Grant from Cancer Research UK (RG66287, A15874). OCCAMS2 was funded by a Programme Grant from Cancer Research UK (RG81771/RG84119, A22720/A22131). Funding Information: The GO2 trial was funded by Cancer Research UK (trial number: CRUK/12/022) and ran within the UK National Health Service and was supported by the National Institute for Health Research (NIHR) Clinical Research Network. HIG is supported in part by the National Institute for Health and Care Research (NIHR) Leeds Biomedical Research Centre. Funders had no role in designing, undertaking or reporting the study, and the views expressed in this publication are those of the author(s) and not necessarily those of the funders, NHS or the UK Department of Health and Social Care. This trial ran within the UK National Health Service and was supported by the National Institute for Health Research (NIHR) Clinical Research Network. Publisher Copyright: {\textcopyright} 2024 The Authors",
year = "2024",
month = may,
day = "1",
doi = "10.1016/j.esmoop.2024.103450",
language = "English",
volume = "9",
journal = "ESMO Open",
issn = "2059-7029",
publisher = "BMJ Publishing Group",
number = "5",
}