Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma.
Adenocarcinoma
/ immunology
Aged
Antineoplastic Agents
/ therapeutic use
B7-H1 Antigen
CD8-Positive T-Lymphocytes
Chemotherapy, Adjuvant
DNA Damage
/ immunology
Disease-Free Survival
Esophageal Neoplasms
/ immunology
Esophagectomy
Female
Humans
Male
Middle Aged
Neoadjuvant Therapy
Predictive Value of Tests
Survival Rate
Treatment Outcome
Dna damage
chemotherapy
immune response
oesophageal cancer
Journal
Gut
ISSN: 1468-3288
Titre abrégé: Gut
Pays: England
ID NLM: 2985108R
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
19
09
2018
revised:
13
02
2019
accepted:
15
02
2019
pubmed:
11
3
2019
medline:
2
11
2019
entrez:
11
3
2019
Statut:
ppublish
Résumé
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. 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). 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). 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.
Identifiants
pubmed: 30852560
pii: gutjnl-2018-317624
doi: 10.1136/gutjnl-2018-317624
pmc: PMC6839732
doi:
Substances chimiques
Antineoplastic Agents
0
B7-H1 Antigen
0
CD274 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1918-1927Subventions
Organisme : Medical Research Council
Pays : United Kingdom
Organisme : Cancer Research UK
ID : RG66287
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Investigateurs
Ayesha Noorani
(A)
Paul Aw Edwards
(PA)
Nicola Grehan
(N)
Barbara Nutzinger
(B)
Caitriona Hughes
(C)
Elwira Fidziukiewicz
(E)
Jason Crawte
(J)
Alex Northrop
(A)
Gianmarco Contino
(G)
Xiaodun Li
(X)
Rachel De La Rue
(R)
Maria O'donovan
(M)
Shalini Malhotra
(S)
Monika Tripathi
(M)
Simon Tavaré
(S)
Andy G Lynch
(AG)
Matthew Eldridge
(M)
Lawrence Bower
(L)
Ginny Devonshire
(G)
Sriganesh Jammula
(S)
Jim Davies
(J)
Charles Crichton
(C)
Nick Carroll
(N)
Peter Safranek
(P)
Andrew Hindmarsh
(A)
Vijayendran Sujendran
(V)
Stephen J Hayes
(SJ)
Yeng Ang
(Y)
Shaun R Preston
(SR)
Sarah Oakes
(S)
Izhar Bagwan
(I)
Vicki Save
(V)
Richard Je Skipworth
(RJ)
Ted R Hupp
(TR)
Olga Tucker
(O)
Andrew Beggs
(A)
Philippe Taniere
(P)
Sonia Puig
(S)
Jack Owsley
(J)
Hugh Barr
(H)
Neil Shepherd
(N)
Oliver Old
(O)
Jesper Lagergren
(J)
James Gossage
(J)
Andrew Davies
(A)
Fuju Chang
(F)
Janine Zylstra
(J)
Ula Mahadeva
(U)
Vicky Goh
(V)
Francesca D Ciccarelli
(FD)
Grant Sanders
(G)
Richard Berrisford
(R)
Catherine Harden
(C)
Mike Lewis
(M)
Ed Cheong
(E)
Bhaskar Kumar
(B)
Simon L Parsons
(SL)
Irshad Soomro
(I)
Philip Kaye
(P)
John Saunders
(J)
Laurence Lovat
(L)
Rehan Haidry
(R)
Laszlo Igali
(L)
Michael Scott
(M)
Sharmila Sothi
(S)
Sari Suortamo
(S)
Suzy Lishman
(S)
George B Hanna
(GB)
Krishna Moorthy
(K)
Christopher J Peters
(CJ)
Anna Grabowska
(A)
Helen Coleman
(H)
Commentaires et corrections
Type : CommentIn
Informations de copyright
© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: LAK, AMM, SMW, DPH and RK are employees of Almac Diagnostics and have patent declarations. GEL and CJS are employees of Almac Diagnostics.
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