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.
Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma / R. Turkington, L. Knight, J. Blayney, M. Secrier, R. Douglas, E. Parkes, E. Sutton, L. Stevenson, D. Mcmanus, S. Halliday, A. Mccavigan, G. Logan, S. Walker, C. Steele, J. Perner, J. Bornschein, S. Macrae, A. Miremadi, E. Mccarron, S. Mcquaid, K. Arthur, J. James, M. Eatock, R. O'Neill, F. Noble, T. Underwood, D. Harkin, M. Salto-Tellez, R. Fitzgerald, R. Kennedy, A. Noorani, P. Edwards, N. Grehan, B. Nutzinger, C. Hughes, E. Fidziukiewicz, J. Crawte, A. Northrop, G. Contino, X. Li, R. de la Rue, M. O'Donovan, S. Malhotra, M. Tripathi, S. Tavare, A. Lynch, M. Eldridge, L. Bower, G. Devonshire, S. Jammula, J. Davies, C. Crichton, N. Carroll, P. Safranek, A. Hindmarsh, V. Sujendran, S. Hayes, Y. Ang, S. Preston, S. Oakes, I. Bagwan, V. Save, R. Skipworth, T. Hupp, O. Tucker, A. Beggs, P. Taniere, S. Puig, J. Owsley, H. Barr, N. Shepherd, O. Old, J. Lagergren, J. Gossage, A. Davies, F. Chang, J. Zylstra, U. Mahadeva, V. Goh, F. Ciccarelli, G. Sanders, R. Berrisford, C. Harden, M. Lewis, E. Cheong, B. Kumar, S. Parsons, I. Soomro, P. Kaye, J. Saunders, L. Lovat, R. Haidry, L. Igali, M. Scott, S. Sothi, S. Suortamo, S. Lishman, G. Hanna, K. Moorthy, C. Peters, A. Grabowska, H. Coleman. - In: GUT. - ISSN 0017-5749. - 68:11(2019), pp. 1918-1927. [10.1136/gutjnl-2018-317624]
Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma
F. Ciccarelli;
2019
Abstract
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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