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

Abstract

ObjectiveCurrent 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.DesignTranscriptional 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).ResultsA 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).ConclusionThe 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.

Supplementary granulocyte macrophage colony‐stimulating factor to chemotherapy and programmed death‐ligand 1 blockade decreases local recurrence after surgery in bladder cancer

“…A recent paper showed that a profile of DNA damage-associated immune responses is a strong predictor of the benefits of DNA-damaging neoadjuvant chemotherapy in a NAC setting. 40 An additional IHC analysis of resection specimens matched to patients based on gene expression showed a significant association between DNA damage-associated immune response positivity and intratumoral/stromal PD-L1 expression. This finding suggested that PD-L1 expression in the tumor environment is upregulated in tumor cells as a mechanism to resist cytotoxic stress from DNA-damaging chemotherapy.…”

“…One of the important findings of the present study is that GC systemic chemotherapy can upregulate PD‐L1 expression in BCa cells both in vitro and in vivo (Figure A and B). A recent paper showed that a profile of DNA damage‐associated immune responses is a strong predictor of the benefits of DNA‐damaging neoadjuvant chemotherapy in a NAC setting …”

Transcriptomic biomarkers for predicting response to neoadjuvant treatment in oesophageal cancer

“…Turkington et al . validated a 44-gene assay previously developed in breast cancer, the DNA damage immune response (DDIR) assay, in routine clinical formalin-fixed paraffin-embedded (FFPE) biopsies increasing the clinical applicability of this biomarker [ 47 ]. McLaren et al .…”

A Review on Curability of Cancers: More Efforts for Novel Therapeutic Options Are Needed

“…The main hindrance to limited anti-cancer activity in chemotherapy is heterogeneous sensitivity in the diverse cancer cell population: indolent or insensitive cancer cells is the major resource of relapse [125]. Heterogeneous sensitivity can also be observed on an individual level: (1) response rate for solid tumours is generally lower than 50%, with 20–30% in NSCLC [126]; (2) highly responsive patients can be identified by biomarkers, including DNA damage immune response assay, promoter methylation for oesophageal adenocarcinoma patients, and 21-Gene Recurrence Score Prognostic Assay in early breast cancer patients [38,127,128,129]; and (3) higher response rate of pemetrexed in lung adenocarcinoma [130]. Accordingly, the role of chemotherapy in less-responsive cancer types has been challenged by targeted therapy or immunotherapy.…”