Study to determine novel biomarkers for early diagnosis and to inform therapeutic management of Oesophageal Squamous Cell Dysplasia and Carcinoma.
Oesophageal cancer is the 8th most common cancer and the 6th most common cause of cancer death in the world. It is estimated that in 2008 there were 482,000 new cases of oesophageal cancer, and 407,000 oesophageal cancer deaths, and that 83% of the cases and 86% of the deaths occurred in developing countries.
With the current best clinical management, the 5-year relative survival rate of oesophageal cancer in the Western Countries is 19%, but significantly lower (<10%) in developing countries. The main reason for this poor survival is symptomatic presentation of cancer frequently occur at advanced stage with invasion deep into the oesophageal wall and/or metastasis in lymph nodes and other organs, making success rate of curative therapy low.
Types of oesophageal cancers
The two main types of oesophageal cancer described are Oesophageal Squamous Cell Carcinoma (OSCC) and Adenocarcinoma. In the case of OSCC, the risk factors and the genetic events driving it include:
1) Lifestyle and environmental factors: OSCC is specifically associated with polymorphisms in genes called ALDH2 and ADH1B1, both involved in alcohol metabolism and CYP1A1, involved in xenobiotic detoxification. Smoking, even in the absence of alcohol consumption, increases the risk for OSCC by 50% for every extra 10 cigarettes/day, with a maximum risk at 40 cigarettes per day. The combined exposure to tobacco and alcohol has a synergistic effect that fuels the cancer formation processes
2) Genetic factors: Familial occurrences, for example in a genetic condition called tylosis, a rare autosomal dominant skin disorder characterised by hyperkeratosis of the soles and palms, which leads to an increased risk of oesophageal squamous cell carcinoma with a penetrance of 95% by age 65.
Stages in the development of OSCC
Squamous cell dysplasia has been described to precede the development of invasive OSCC through a step-wise transition from low-grade dysplasia (LGD), high grade dysplasia (HGD) and mucosal carcinoma. However, the molecular alterations leading to the pre-malignant stages and its progression to invasive cancer are less well understood and have been vastly under studied to date.
Relevance of our experience
As the Fitzgerald group have demonstrated in the case of Barrett's oesophagus (premalignant columnar metaplasia) and oesophageal adenocarcinoma, understanding the molecular events underlying carcinogenesis is the first steps to developing novel diagnostic tests for initial diagnosis, risk stratification (e.g. trefoil factor 3, p53, AOL) and prognosis (e.g. prognostic gene signatures), as well as enabling the identification of potential therapeutic targets (e.g. Trim44).
The Kelsell group recently identified RHBDF2 gene as the underlying cause of the inherited OSCC in the Tylosis patients and there is evidence that this gene may also be dysregulated in sporadic cases.
OSCAR Study Hypothesis
The molecular alterations that characterise, and in some circumstances drive, the initiation and development of OSCC can be used to develop clinically relevant diagnostic biomarkers to improve early diagnosis, tumour classification and therapeutic management.
Aims of the OSCAR Study
• Identify key molecular changes that occur as squamous dysplasia develops and progresses into invasive OSCC
• Develop clinical assays for early detection of disease
• Develop and validate improved staging and prognostic algorithms based on molecular biomarkers to inform therapeutic decisions
- Individuals 18 years old and above at the time of the procedure (endoscopy or surgery)
- Ability to provide informed consent for procedures or diagnostic sample use
- Patient at high risk for squamous cell dysplasia (smoker with weekly intake of alcohol of 26 units or more) OR
- Patients referred to endoscopy as part of the regular dysplasia follow up OR
- Patients referred for endoscopic screening on a background of previously treated head and neck primary cancer OR
- Individual from a family with tylosis with a confirmed germline mutation in RHBDF2
- Control patient with oesophageal biopsies taken for suspicion of peptic oesophagitis, eosinophilic oesophagitis, candidiasis, sub-epithelial lesions or other oesophageal pathology, but normal histological finding
- For individual procedures as below:
i. Blood samples: People on anticoagulation therapy/medication (warfarin, clopidogrel, heparin or tinzaparin) for high risk conditions, which preclude possibility to stop the medication
ii. Cytosponge™ samples :
- Individuals with symptoms of dysphagia
- Current history of active oro-pharyngeal cancer
- Oesophageal varices, stricture or requiring dilatation of the oesophagus
- On anticoagulation therapy/medication (warfarin, clopidogrel, heparin or tinzaparin) for high risk conditions, which preclude possibility to stop the medication without bridging with heparin
- Individuals who have had a myocardial infarction or any cardiac event less than six months prior to recruitment into the study
- Individuals who have had a cerebrovascular event less than 6 months ago where their swallowing has been affected
iii. Endoscopic biopsies
- On anticoagulation therapy/medication (warfarin, clopidogrel, heparin or tinzaparin) on the day of their procedure
- Individuals who have had a myocardial infarction or any cardiac event less than 6 months prior to recruitment into the study
iV. Probe-based confocal laser endo-microscopy (not relevant to the Cancer group)
- Severe asthma
- Allergy to fluorescein
V. Control patients, presence of significant inflammation (including eosinophilic infiltrate) or candidiasis.
Clinical application strategy of the Oscar study
In order to make a step change in survival, a significant effort is required at several points in the clinical pathway ranging from improved prevention strategies, early diagnosis and screening programmes, improved prognostic tools as well as the advancement in therapeutic approaches. The alternative strategy that is well developed and is in use in the Adenocarcinoma type management has been secondary prevention through screening programs combined with therapeutic intervention for the early stages of the disease - Barrett's oesophagus. These strategy that combines endoscopic treatment with radiofrequency ablation in patients with LGD and HGD, significantly reduces incidence of cancer in randomised controlled trials
Our research groups have significant track record of studies in the context of oesophageal adenocarcinoma. Having learnt invaluable lessons in our efforts to develop novel clinically applicable modalities for OAC, we are drawing parallels in the methodology employed to identify clinically viable markers for managing squamous dysplasia and OSCC.
Chief Investigator: Professor Rebecca Fitzgerald, MD
Joint Sponsors: MRC Cancer Unit, University of Cambridge and
Cambridge University Hospitals NHS Foundation Trust (CUTH)
Funding from Cancer Research UK (grant number C7570/A19107)
Professor David Kelsell, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London.
Dr Janet Risk, Department of Molecular and Clinical Cancer Medicine, the University of Liverpool, Liverpool, UK
Dr Tony Ellis: Royal Liverpool and Broad-green University, Hospitals, Liverpool, UK
Ms. Zarah Abdullahi, MRC Cancer Unit, University of Cambridge, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, Tel: 01223 763994 / 01223 348667 or
By email: za223@mrc-cu.cam.ac.uk
Professor Rebecca Fitzgerald, MRC Cancer Unit, University of Cambridge, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, Tel: 01223 763287 or
By email: rcf29@mrc-cu.cam.ac.uk
Bird-Lieberman EL, Dunn JM, Coleman HG, Lao-Sirieix P, Oukrif D, Moore CE, et al. Population-Based Study Reveals New Risk-Stratification Biomarker Panel for Barrett's Esophagus. Gastroenterology. 2012 Oct; 143(4):927-35 e3.
Lao-Sirieix P, Caldas C, Fitzgerald RC. Genetic predisposition to gastro-oesophageal cancer. Curr Opin Genet Dev. 2010 Jun; 20(3):210-7.
Morita M, Kumashiro R, Kubo N, Nakashima Y, Yoshida R, Yoshinaga K, et al. Alcohol drinking, cigarette smoking, and the development of squamous cell carcinoma of the esophagus: epidemiology, clinical findings, and prevention. Int J Clin Oncol. 2010 2010/04/01; 15(2):126-34.
Pandeya N, Williams G, Green AC, Webb PM, Whiteman DC. Alcohol Consumption and the Risks of Adenocarcinoma and Squamous Cell Carcinoma of the Esophagus. Gastroenterology. 2009; 136(4):1215-24.e2.
Pandeya N, Williams GM, Sadhegi S, Green AC, Webb PM, Whiteman DC. Associations of Duration, Intensity, and Quantity of Smoking with Adenocarcinoma and Squamous Cell Carcinoma of the Esophagus. American Journal of Epidemiology. 2008 July 1, 2008; 168(1):105-14.
Phoa KN, van Vilsteren FG, Weusten BL, Bisschops R, Schoon EJ, Ragunath K, et al. Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial. JAMA. 2014 Mar 26; 311(12):1209-17.
Ross-Innes CS, Debiram-Beecham I, O'Donovan M, Walker E, Varghese S, Lao-Sirieix P, et al. Evaluation of a minimally invasive cell sampling device coupled with assessment of trefoil factor 3 expression for diagnosing Barrett's esophagus: a multi-center case-control study. PLoS Med. 2015 Jan; 12(1):e1001780.
Blaydon DC, Etheridge SL, Risk JM, Hennies HC, Gay LJ, Carroll R, et al. RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome. Am J Hum Genet. 2012 Feb 10; 90(2):340-6.
BEST3 (Cytosponge) trial
International cancer genome consortium
Heartburn Cancer UK