Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma. Issue 11 (9th March 2019)

• Record Type: Journal Article
• Authors: Turkington, Richard C; Knight, Laura A; Blayney, Jaine K; Secrier, Maria; Douglas, Rosalie; Parkes, Eileen E; Sutton, Eilis K; Stevenson, Leanne; McManus, Damian; Halliday, Sophia; McCavigan, Andrena M; Logan, Gemma E; Walker, Steven M; Steele, Christopher J; Perner, Juliane; Bornschein, Jan; MacRae, Shona; Miremadi, Ahmad; McCarron, Eamon; McQuaid, Stephen; Arthur, Kenneth; James, Jacqueline A; Eatock, Martin M; O'Neill, Robert; Noble, Fergus; Underwood, Timothy J; Harkin, D Paul; Salto-Tellez, Manuel; Fitzgerald, Rebecca C; Kennedy, Richard D
• Other Names: author non-byline.; Noorani Ayesha author non-byline.; Edwards Paul Aw author non-byline.; Grehan Nicola author non-byline.; Nutzinger Barbara author non-byline.; Hughes Caitriona author non-byline.; Fidziukiewicz Elwira author non-byline.; Crawte Jason author non-byline.; Northrop Alex author non-byline.; Contino Gianmarco author non-byline.; Li Xiaodun author non-byline.; La rue Rachel De author non-byline.; O'donovan Maria author non-byline.; Malhotra Shalini author non-byline.; Tripathi Monika author non-byline.; Tavaré Simon author non-byline.; Lynch Andy G author non-byline.; Eldridge Matthew author non-byline.; Bower Lawrence author non-byline.; Devonshire Ginny author non-byline.; Jammula Sriganesh author non-byline.; Davies Jim author non-byline.; Crichton Charles author non-byline.; Carroll Nick author non-byline.; Safranek Peter author non-byline.; Hindmarsh Andrew author non-byline.; Sujendran Vijayendran author non-byline.; Hayes Stephen J author non-byline.; Ang Yeng author non-byline.; Preston Shaun R author non-byline.; Oakes Sarah author non-byline.; Bagwan Izhar author non-byline.; Save Vicki author non-byline.; Skipworth Richard Je author non-byline.; Hupp Ted R author non-byline.; Tucker Olga author non-byline.; Beggs Andrew author non-byline.; Taniere Philippe author non-byline.; Puig Sonia author non-byline.; Owsley Jack author non-byline.; Barr Hugh author non-byline.; Shepherd Neil author non-byline.; Old Oliver author non-byline.; Lagergren Jesper author non-byline.; Gossage James author non-byline.; Davies, Andrew author non-byline.; Chang Fuju author non-byline.; Zylstra Janine author non-byline.; Mahadeva Ula author non-byline.; Goh Vicky author non-byline.; Ciccarelli Francesca D author non-byline.; Sanders Grant author non-byline.; Berrisford Richard author non-byline.; Harden Catherine author non-byline.; Lewis Mike author non-byline.; Cheong Ed author non-byline.; Kumar Bhaskar author non-byline.; Parsons Simon L author non-byline.; Soomro Irshad author non-byline.; Kaye Philip author non-byline.; Saunders John author non-byline.; Lovat Laurence author non-byline.; Haidry Rehan author non-byline.; Igali Laszlo author non-byline.; Scott Michael author non-byline.; Sothi Sharmila author non-byline.; Suortamo Sari author non-byline.; Lishman Suzy author non-byline.; Hanna George B author non-byline.; Moorthy Krishna author non-byline.; Peters Christopher J author non-byline.; Grabowska Anna author non-byline.; Coleman Helen author non-byline.;
• Is Part Of: Gut. Volume 68:Issue 11(2019)
• Page Start: 1918
• Page End: 1927
• Publication Date: 2019-03-09
• Subjects: oesophageal cancer -- chemotherapy -- Dna damage -- immune response; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2018-317624
• Languages: English
• ISSNs: 0017-5749

Abstract

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.