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Randomized Controlled Trial
. 2024 May;9(5):103450.
doi: 10.1016/j.esmoop.2024.103450. Epub 2024 May 13.

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

M A Baxter  1 , L C Spender  2 , D Cairns  3 , S Walsh  4 , R Oparka  4 , R J Porter  5 , S Bray  6 , G Skinner  6 , S King  6 , J Turbitt  7 , D Collinson  7 , Z H Miedzybrodzka  8 , G Jellema  9 , G Logan  9 , R D Kennedy  10 , R C Turkington  10 , M H McLean  11 , D Swinson  12 , H I Grabsch  13 , S Lord  14 , M J Seymour  15 , P S Hall  16 , R D Petty  17
Affiliations
Randomized Controlled Trial

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

M A Baxter et al. ESMO Open. 2024 May.

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.

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Conflict of interest statement

Disclosure 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.

Figures

Figure 1
Figure 1
Kaplan–Meier curves stratified by DDIR status for (A) progression-free and (B) overall survival for 243 patients with advanced gastroesophageal adenocarcinoma treated with platinum-based chemotherapy in the GO2 trial and (C) progression-free and (D) overall survival for the subgroup of 82 patients treated with full dose platinum-based chemotherapy. CI, confidence interval; DDIR, DNA damage immune response; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.
Figure 2
Figure 2
(A) Microenvironment cell population (MCP) scores of the individual immune cell types according to DDIR status. (B) Increased immune infiltrates correlated highly with DDIR positivity. MCP scores of three immune infiltrates—T-cells (blue), B lineage (red), and monocytic lineage (green)—correlated with DDIR scores with a line of best fit for each immune infiltrate. The black dashed horizontal line denotes the DDIR positivity cut-off. (C) Cytotoxic lymphocyte MCP scores correlated with DDIR scores in the GO2 population. The black horizontal line denotes the cut-off for DDIR positivity. Boxplot denotes the distribution of values for DDIR-positive and -negative status in the cohort. DDIR, DNA damage immune response; NEG, DDIR-negative; NK, natural killer; POS, DDIR-positive.
Figure 3
Figure 3
(A) Correlation of CD274 RNA expression and DDIR Score in the GO2 GOA population. The black line denotes DDIR positivity. Boxplot denotes distribution of values for DDIR-positive and negative in the cohort. (B) Correlation of MSI Signature RNA expression score and DDIR Score in the GO2 GOA population. The black line denotes DDIR positivity. Boxplot denotes distribution of values for DDIR-positive and negative in the cohort. DDIR, DNA damage immune response; MSI, microsatellite instability.
Figure 4
Figure 4
(A) Correlation between raw DDIR signature score and CXCL10 RNA expression (FPKM) in the GO2 adenocarcinoma population. Boxplot denotes the distribution of expression values for the DDIR-positive and -negative samples in the cohort. (B) Overall survival in the GO2 adenocarcinoma population according to CXCL10 RNA expression (FPKM). Low—bottom 25%, middle—25%–75%, high—top 25%. (C) Cox regression analysis for overall survival incorporating CXCL10 RNA expression group. ∗indicates P-value <0.05. (D) Correlation between raw DDIR signature score and CXCL10/CCL5 RNA expression (FPKM) signature in the GO2 adenocarcinoma population. Boxplot denotes distribution of values for DDIR-positive and -negative in the cohort. AIC, Akaike's Information Criterion; DDIR, DNA damage immune response; ECOG, Eastern Cooperative Oncology Group; GOJ, gastroesophageal junction.
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