An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma.

Baxter, MA.; Spender, LC.; Cairns, D.; Walsh, S.; Oparka, R.; Porter, RJ.; Bray, S.; Skinner, G.; King, S.; Turbitt, J.; Collinson, D.; Miedzybrodzka, ZH.; Jellema, G.; Logan, G.; Kennedy, RD.; Turkington, RC.; McLean, MH.; Swinson, D.; Grabsch, HI.; Lord, S.; Seymour, MJ.; Hall, PS.; Petty, RD.

An investigation of the clinical impact and therapeutic relevance of a DNA damage immune response (DDIR) signature in patients with advanced gastroesophageal adenocarcinoma.

All Authors

Baxter, MA.

Spender, LC.

Cairns, D.

Walsh, S.

Oparka, R.

Porter, RJ.

Bray, S.

Skinner, G.

King, S.

Turbitt, J.

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LTHT Author

Swinson, Daniel
Seymour, Matt

LTHT Department

Oncology

Publication Date

2024

Item Type

Journal Article
Randomized Controlled Trial

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.