Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma.
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Date
2019-11-01ICR Author
Author
Turkington, RC
Knight, LA
Blayney, JK
Secrier, M
Douglas, R
Parkes, EE
Sutton, EK
Stevenson, L
McManus, D
Halliday, S
McCavigan, AM
Logan, GE
Walker, SM
Steele, CJ
Perner, J
Bornschein, J
MacRae, S
Miremadi, A
McCarron, E
McQuaid, S
Arthur, K
James, JA
Eatock, MM
O'Neill, R
Noble, F
Underwood, TJ
Harkin, DP
Salto-Tellez, M
Fitzgerald, RC
Kennedy, RD
Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Study Group,
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Study Group
CD8-Positive T-Lymphocytes
Humans
Adenocarcinoma
Esophageal Neoplasms
DNA Damage
Antineoplastic Agents
Disease-Free Survival
Treatment Outcome
Chemotherapy, Adjuvant
Neoadjuvant Therapy
Esophagectomy
Survival Rate
Predictive Value of Tests
Aged
Middle Aged
Female
Male
B7-H1 Antigen
Research team
Integrated Pathology
Language
eng
Date accepted
2019-02-15
License start date
2019-11
Citation
Gut, 2019, 68 (11), pp. 1918 - 1927
Publisher
BMJ PUBLISHING GROUP