Patients with oesophageal adenocarcinoma have a median survival of 1 year, despite advances in treatment.1 The burden of oesophageal adenocarcinoma could be reduced by diagnosing more cases of the precursor lesion Barrett's oesophagus while identifying individuals at increased risk for cancer development before treating them endoscopically.2 However, this is a formidable task given that the incidence of gastro-oesophageal reflux is approximately five per 1000 person-years (15% incidence) in the UK and Europe.3 Furthermore, despite clinical guidelines for endoscopic referral, primary care practice varies and low endoscopy referral rates correlate with poor outcomes from oesophageal cancer.4 The scale of the problem and the psychological and fiscal costs of endoscopy necessitate a new strategy.
We have developed a non-endoscopic diagnostic test involving a cell-collection device that, coupled with the biomarker trefoil factor 3 (TFF3), diagnoses Barrett's oesophagus.5, 6 The device, called Cytosponge, comprises a medical-grade foam sphere on a string compressed within a gelatine capsule that is swallowed while holding onto the string. After 5 min, the capsule dissolves in the stomach, allowing the foam sphere to expand before being pulled from the stomach through the oesophagus to the mouth. Cells are collected along the entire oesophageal lining, minimising the sampling bias that is inevitable with endoscopic biopsies. The sample is transported to the laboratory in preservative at room temperature and processed to paraffin for TFF3 biomarker assessment. Data from previously published studies, amounting to more than 2000 patients, have shown that this approach is safe, has favourable acceptability compared with endoscopy, has a sensitivity of 79·5–87% (depending on Barrett's oesophagus segment length), and has a specificity of 92·4% for diagnosing Barrett's oesophagus.5, 6
Research in context
Evidence before this study
We searched PubMed from database inception to Sept 1, 2011, with the MeSH terms: “biomarkers”, “cancer progression”, and “Barrett's oesophagus” before the start of the BEST2 trial, in order to review the status of the scientific literature. This important area has attracted a lot of attention, and aside from the histopathological assessment of dysplasia, the most promising biomarkers include P53 status, copy number alterations, and methylation panels. All of these studies have relied on endoscopic sampling, which is invasive and resource intensive. Furthermore, most effort has focused on identifying patients at high risk for cancer. However, since most Barrett's oesophagus cases will not progress to cancer, strategies to risk-stratify patients and avoid overdiagnosis are also very important. Furthermore, given the heterogeneity in the molecular genetic patient profiles of those progressing to cancer, identification of very low-risk patients might be a more achievable biomarker strategy. A non-endoscopic cell collection device (Cytosponge) is effective at diagnosing Barrett's oesophagus when coupled with the biomarker, TFF3. The aim of this study was to determine whether additional biomarkers could identify patients at very low risk of cancer, in whom further monitoring could be performed via the Cytosponge. Endoscopy and treatment could then focus on the patients at highest risk.
Added value of this study
We tested a clinical and molecular biomarker panel on Cytosponge samples (seven variables) and used multivariable logistic regression to identify a minimum panel that could risk-stratify patients. The optimum panel comprises age, length of Barrett's oesophagus segment, waist-to-hip ratio (or body-mass index), and three biomarkers scored in a binary method to indicate P53 status, Aurora kinase A expression, and glandular atypia, and divides patients into low-risk, moderate-risk and high-risk groups. This risk score was validated in an independent patient cohort and shown to confidently identify approximately 30% of patients with a low risk for malignant progression. The high-risk and moderate-risk patients would be triaged for endoscopy, which could be prioritised accordingly. To the best of our knowledge, this is the first multidimensional panel applied to non-endoscopic oesophageal cell samples (ie, one involving DNA mutation, protein expression, and clinical variables) to determine the risk profile for a patient with Barrett's oesophagus.
Implications of all the available evidence
At present, the monitoring of patients with diagnosed Barrett's oesophagus relies on endoscopy, which is invasive for patients and expensive for the health-care system. The use of a Cytosponge-biomarker test has the potential to more objectively risk-stratify patients and identify a low-risk group for monitoring within the primary care setting that could be spared endoscopy.
For TFF3-positive patients, it is essential that additional biomarkers are tested to assess the presence of genetic or molecular abnormalities indicative of dysplasia, because positive tests in patients with very benign disease at low risk of progression are common in early cancer detection.7 Overdiagnosis and overtreatment have adverse consequences for both patients and health-care providers.8 Our primary goal is thus to identify patients with Barrett's oesophagus with a very-low-risk profile, so that these individuals can be reassured without having to undergo endoscopy.
We have shown that TP53 mutations qualify for a risk stratification biomarker and are detectable using the Cytosponge.9 We have also shown that the Cytosponge sample is representative of the multiple clones within a diverse genetic content.10 However, for a risk-stratification tool to be clinically applicable, it is important not to miss patients with high-grade dysplasia and intramucosal adenocarcinoma. Although TP53 mutation has a high specificity, it will not identify all patients with high-grade dysplasia or early cancer because its prevalence is 70–80%.9, 11 To increase sensitivity for high-risk patients with Barrett's oesophagus, we propose including additional molecular biomarkers combined with clinical factors.
Hence, we aimed to identify a clinically applicable risk-stratification biomarker panel that could be used on the Cytosponge samples; to apply this panel to a large cohort of patients with Barrett's oesophagus and a TFF3-positive Cytosponge sample to confidently identify a low-risk group of at least 30% of cases who could be spared endoscopy; and to test the Cytosponge risk-stratification model on an independent cohort of patients.