Biomarker qualification in Barrett s oesophagus

Lead Research Organisation: Medical Research Council
Department Name: Medical Research Council

Abstract

A type of oesophageal or gullet cancer, called adenocarcinoma, is rapidly increasing in the western world. Most patients do not seek medical attention until they develop swallowing difficulties and by then the cancer is usually advanced with a 5-year survival of 20%. However, if the cancer is detected early then the survival rate can be improved to 80%. These cancers usually develop as a complication of a condition called Barrett?s oesophagus. However, most people in the population with Barrett?s oesophagus will not develop cancer. Therefore research is needed to identify the patients at greatest risk for oesophageal cancer. In this grant we are testing some promising molecular tools to see whether they can predict cancer progression using a large clinical biopsy resource from the Northern Ireland Barrett s Oeospagus Register. If we could find a molecular test that predicted cancer development this would prevent many patients with Barrett s oeosphagus having unecessary endoscopy examinations and enable us to target resources to patients at highest risk.

Technical Summary

Introduction: The incidence of oesophageal adenocarcinoma (OAC) is increasing dramatically in the west and has a very poor prognosis. Barrett?s oesophagus (BE) is an established risk factor for OAC. Currently, BE patients are offered regular endoscopy (surveillance) to detect cancerous changes early. This hinges on the subjective histopathological assessment of multiple, random biopsies which is problematic. Biomarkers have the potential to reduce sampling bias and improve the risk-stratification of patients. Since endoscopy is invasive, unpleasant and costly, ideally biomarkers should be developed for non-endoscopic applications. Biomarkers for this study have therefore been selected on the basis of their mechanistic role, abundance and ease of detection.
Hypothesis: Molecular biomarkers (aneuploidy, cyclin A, lectins) have the potential to risk stratify BE patients. In addition because these changes occur at the epithelial surface and are abundant there is the potential to develop these markers for cytological screening (aneuploidy, cyclin A) and for novel fluorescent endoscopic diagnostic methods (lectins).
Aims: 1. Determine whether specific biomarkers can predict cancer risk in a highly characterised, population-based BE cohort. 2. Use biomarkers, appropriately qualified in phase 1, to develop: a) a quantitative assay for assessment of biomarker(s) from a cytological specimen, b) a lectin-probe suitable for fluorescence imaging detectable at endoscopy.
Study design: Phase 3 retrospective longitudinal repository study using a nested case-control approach within the N Ireland BE Register (NIBR). The NIBR includes every adult identified with BE within NI (population 1.7 million) between 1993-2005. Cases are 108 BE patients who have progressed to OAC or HGD, compared with 3 controls per patient (matched for age, sex and year of diagnosis) who have not progressed to these states; (OAC incidence 0.4% per year, HGD incidence 0.08% per year) from a total of 23,771 person years of follow-up. The expression of cyclin A (immunohistochemistry), lectins (HPA, PNA, WGA, CON-A), (fluorescence histochemistry) and aneuploidy (image cytometric analysis) will be determined in biopsies at specific time intervals. For the assay development, cytological samples (n=1000) will be taken from ongoing surveillance programmes in Cambridge, Belfast and UCLH. These patients are well characterised with longitudinal data over 5 years. This well established cohort affords our industrial partner GSK the opportunity to examine genetic aberrations in ERBB2 as a prelude to a clinical chemoprevention trial.
Clinical benefit: The use of biomarkers will benefit patients with BE by enabling accurate assessment of cancer risk and providing reliable surrogate endpoints for intervention studies.

Publications

10 25 50
 
Description Digistain meets "Cytosponge"- a new technology for early detection of Oesophagael Cancer
Amount £246,552 (GBP)
Funding ID IA160044 
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 04/2017 
End 03/2019
 
Description Evaluation of the Elsevier ELN Tool
Amount £160,000 (GBP)
Organisation Elsevier 
Sector Private
Country Netherlands
Start 01/2017 
End 03/2019
 
Description GSK Project grant
Amount £136,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 11/2007 
End 10/2010
 
Description Mechanistically informed Phenotypic Screening to Advance New Therapeutic Treatments for Oesophageal Cancer Patients
Amount £260,860 (GBP)
Funding ID A24892 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2018 
End 02/2020
 
Description Medtronic Barrett's oEsophagus Trial 3 (Best3): Cluster randomised controlled trial comparing the cytosponge with usual care to facilitate the diagnosis of oesophageal pre-cancer in primary care
Amount $189,828 (USD)
Funding ID ISR-TEMP1150 
Organisation Medtronic 
Sector Private
Country United States
Start 11/2016 
End 12/2019
 
Title Cytosponge screening device 
Description A new screening tool was developed and patented which involves a cell collection device suitable for primary care in combination with a molecular marker 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact PMID: 19651633 [PubMed - in process] 
URL http://europepmc.org/abstract/MED/19651633
 
Title up to date population based cohort database Barrett's samples 
Description The grant funding covered infrastructure and staff support for the Northern Ireland Population Register of Barrett's oesophagus 
Type Of Material Biological samples 
Provided To Others? No  
Impact still in progress 
 
Description OCCAMS (Oesophageal Cancer Clinical and Molecular Staging) 
Organisation Addenbrooke's Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution We set up this UK multicentre collaboration which currently includes 10 centres from around the UK
Collaborator Contribution Shared dataShared dataShared dataShared dataShared dataShared dataShared dataShared dataShared dataShared data
Impact PMID: 19526624 PMID: 20621683
Start Year 2007
 
Description OCCAMS (Oesophageal Cancer Clinical and Molecular Staging) 
Organisation Bristol Royal Infirmary
Country United Kingdom 
Sector Hospitals 
PI Contribution We set up this UK multicentre collaboration which currently includes 10 centres from around the UK
Collaborator Contribution Shared dataShared dataShared dataShared dataShared dataShared dataShared dataShared dataShared dataShared data
Impact PMID: 19526624 PMID: 20621683
Start Year 2007
 
Description OCCAMS (Oesophageal Cancer Clinical and Molecular Staging) 
Organisation Glasgow Royal Infirmary
Country United Kingdom 
Sector Hospitals 
PI Contribution We set up this UK multicentre collaboration which currently includes 10 centres from around the UK
Collaborator Contribution Shared dataShared dataShared dataShared dataShared dataShared dataShared dataShared dataShared dataShared data
Impact PMID: 19526624 PMID: 20621683
Start Year 2007
 
Description OCCAMS (Oesophageal Cancer Clinical and Molecular Staging) 
Organisation Gloucestershire Royal Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution We set up this UK multicentre collaboration which currently includes 10 centres from around the UK
Collaborator Contribution Shared dataShared dataShared dataShared dataShared dataShared dataShared dataShared dataShared dataShared data
Impact PMID: 19526624 PMID: 20621683
Start Year 2007
 
Description OCCAMS (Oesophageal Cancer Clinical and Molecular Staging) 
Organisation Oxford University Hospitals NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution We set up this UK multicentre collaboration which currently includes 10 centres from around the UK
Collaborator Contribution Shared dataShared dataShared dataShared dataShared dataShared dataShared dataShared dataShared dataShared data
Impact PMID: 19526624 PMID: 20621683
Start Year 2007
 
Description OCCAMS (Oesophageal Cancer Clinical and Molecular Staging) 
Organisation Royal Devon and Exeter NHS Foundation Trust
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We set up this UK multicentre collaboration which currently includes 10 centres from around the UK
Collaborator Contribution Shared dataShared dataShared dataShared dataShared dataShared dataShared dataShared dataShared dataShared data
Impact PMID: 19526624 PMID: 20621683
Start Year 2007
 
Description OCCAMS (Oesophageal Cancer Clinical and Molecular Staging) 
Organisation Royal Infirmary of Edinburgh
Country United Kingdom 
Sector Hospitals 
PI Contribution We set up this UK multicentre collaboration which currently includes 10 centres from around the UK
Collaborator Contribution Shared dataShared dataShared dataShared dataShared dataShared dataShared dataShared dataShared dataShared data
Impact PMID: 19526624 PMID: 20621683
Start Year 2007
 
Description OCCAMS (Oesophageal Cancer Clinical and Molecular Staging) 
Organisation University Hospital of Wales
Country United Kingdom 
Sector Hospitals 
PI Contribution We set up this UK multicentre collaboration which currently includes 10 centres from around the UK
Collaborator Contribution Shared dataShared dataShared dataShared dataShared dataShared dataShared dataShared dataShared dataShared data
Impact PMID: 19526624 PMID: 20621683
Start Year 2007
 
Description OCCAMS (Oesophageal Cancer Clinical and Molecular Staging) 
Organisation University Hospitals Birmingham NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution We set up this UK multicentre collaboration which currently includes 10 centres from around the UK
Collaborator Contribution Shared dataShared dataShared dataShared dataShared dataShared dataShared dataShared dataShared dataShared data
Impact PMID: 19526624 PMID: 20621683
Start Year 2007
 
Description OCCAMS (Oesophageal Cancer Clinical and Molecular Staging) 
Organisation University of Bristol
Department School of Clinical Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We set up this UK multicentre collaboration which currently includes 10 centres from around the UK
Collaborator Contribution Shared dataShared dataShared dataShared dataShared dataShared dataShared dataShared dataShared dataShared data
Impact PMID: 19526624 PMID: 20621683
Start Year 2007
 
Description prognostic gene signtaures in oesophageal cancer 
Organisation Merck
Country Germany 
Sector Private 
PI Contribution Research on data provided
Collaborator Contribution Research data
Impact This profiling project would not have been affordable within the programme grant. The data has been invaluable for developing prognostic alogorithm which are now at the validation stage.
 
Title Oesophageal prognostic signature 
Description Four gene signature for use in diagnosis of oesophageal cancer. 
IP Reference GB1005048.2 
Protection Patent application published
Year Protection Granted 2010
Licensed No
Impact development for use in screening PATENT APPLICATION TERMINATED 2011
 
Title Risk stratification (prediction of likelihood) for progression from BE to high grade dysplasia (EAC) 
Description Risk stratification (prediction of likelihood) for progression from Barrett's Esophagus to high grade dysplasia (EAC), using the signature Lectin/DNA content abnormality/CA19-9/CyclinA/p53. 
IP Reference GB1208756.5 
Protection Patent application published
Year Protection Granted 2012
Licensed No
Impact None to date.
 
Title TIME diagnosis of high grade dysplasia 
Description TIME diagnosis of high grade dysplasia (EAC), using Imaging endoscopy (AFI) plus aneuploidy/p53/cyclinA 
IP Reference GB1208963.7 
Protection Patent application published
Year Protection Granted 2012
Licensed No
Impact None to date
 
Title Cytosponge 
Description The Cytosponge is a cell colection device which when coupled with a molecular marker can be used to diagnose Barrett's oesophagus in the primary care setting 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2008
Development Status Under active development/distribution
Clinical Trial? Yes
Impact This has now been awarded funding by CRUK for further evaluation in a large-scale clincial trial 
 
Description Cambridge Science Festival 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Part of 'Mysterious magic to modern marvels' display at Festival with range of activities for children.

improved awareness of science and research.
Year(s) Of Engagement Activity 2009
 
Description MRC Press Release on BMJ paper 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Media release widely picked up by national print and online media such as BBC News Online, Daily Mail, Nursing Times and others.

Greater awareness of research and screening for oesophageal cancer.
Year(s) Of Engagement Activity 2010