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.
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.
Organisations
- Medical Research Council (Lead Research Organisation)
- Bristol Royal Infirmary (Collaboration)
- University Hospitals Birmingham NHS Foundation Trust, Birmingham (Collaboration)
- Royal Infirmary of Edinburgh (Collaboration)
- Glasgow Royal Infirmary (Collaboration)
- University of Bristol, United Kingdom (Collaboration)
- Gloucestershire Royal Hospital (Collaboration)
- Royal Devon and Exeter NHS Foundation Trust (Collaboration)
- Merck (Collaboration)
- Oxford University Hospitals NHS Foundation Trust (Collaboration)
- Addenbrooke's Hospital (Collaboration)
- University Hospital of Wales (Collaboration)
Publications

Kadri SR
(2010)
Acceptability and accuracy of a non-endoscopic screening test for Barrett's oesophagus in primary care: cohort study.
in BMJ (Clinical research ed.)
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 | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2017 |
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 | 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 | OCCAMS (Oesophageal Cancer Clinical and Molecular Staging) |
Organisation | Royal Devon and Exeter 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 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 |