title: Risk stratification of Barrett's oesophagus using a non-endoscopic sampling method coupled with a biomarker panel: a cohort study.
abstract: Barrett's oesophagus predisposes to adenocarcinoma. However, most patients with Barrett's oesophagus will not progress and endoscopic surveillance is invasive, expensive, and fraught by issues of sampling bias and the subjective assessment of dysplasia. We investigated whether a non-endoscopic device, the Cytosponge, could be coupled with clinical and molecular biomarkers to identify a group of patients with low risk of progression suitable for non-endoscopic follow-up.
  
  
  
  In this multicentre cohort study (BEST2), patients with Barrett's oesophagus underwent the Cytosponge test before their surveillance endoscopy. We collected clinical and demographic data and tested Cytosponge samples for a molecular biomarker panel including three protein biomarkers (P53, c-Myc, and Aurora kinase A), two methylation markers (MYOD1 and RUNX3), glandular atypia, and TP53 mutation status. We used a multivariable logistic regression model to compute the conditional probability of dysplasia status. We selected a simple model with high classification accuracy and applied it to an independent validation cohort. The BEST2 study is registered with ISRCTN, number 12730505.
  
  
  
  The discovery cohort consisted of 468 patients with Barrett's oesophagus and intestinal metaplasia. Of these, 376 had no dysplasia and 22 had high-grade dysplasia or intramucosal adenocarcinoma. In the discovery cohort, a model with high classification accuracy consisted of glandular atypia, P53 abnormality, and Aurora kinase A positivity, and the interaction of age, waist-to-hip ratio, and length of the Barrett's oesophagus segment. 162 (35%) of 468 of patients fell into the low-risk category and the probability of being a true non-dysplastic patient was 100% (99% CI 96-100) and the probability of having high-grade dysplasia or intramucosal adenocarcinoma was 0% (0-4). 238 (51%) of participants were classified as of moderate risk; the probability of having high-grade dysplasia was 14% (9-21). 58 (12%) of participants were classified as high-risk; the probability of having non-dysplastic endoscopic biopsies was 13% (5-27), whereas the probability of having high-grade dysplasia or intramucosal adenocarcinoma was 87% (73-95). In the validation cohort (65 patients), 51 were non-dysplastic and 14 had high-grade dysplasia. In this cohort, 25 (38%) of 65 patients were classified as being low-risk, and the probability of being non-dysplastic was 96·0% (99% CI 73·80-99·99). The moderate-risk group comprised 27 non-dysplastic and eight high-grade dysplasia cases, whereas the high-risk group (8% of the cohort) had no non-dysplastic cases and five patients with high-grade dysplasia.
  
  
  
  A combination of biomarker assays from a single Cytosponge sample can be used to determine a group of patients at low risk of progression, for whom endoscopy could be avoided. This strategy could help to avoid overdiagnosis and overtreatment in patients with Barrett's oesophagus.
  
  
  
  Cancer Research UK.
authors.affiliation: MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.
authors.forename: Caryn S
authors.initials: CS
authors.lastname: Ross-Innes
authors.affiliation: MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.
authors.forename: Hamza
authors.initials: H
authors.lastname: Chettouh
authors.affiliation: MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.
authors.forename: Achilleas
authors.initials: A
authors.lastname: Achilleos
authors.affiliation: MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.
authors.forename: Nuria
authors.initials: N
authors.lastname: Galeano-Dalmau
authors.affiliation: MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.
authors.forename: Irene
authors.initials: I
authors.lastname: Debiram-Beecham
authors.affiliation: MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.
authors.forename: Shona
authors.initials: S
authors.lastname: MacRae
authors.affiliation: MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.
authors.forename: Petros
authors.initials: P
authors.lastname: Fessas
authors.affiliation: MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.
authors.forename: Elaine
authors.initials: E
authors.lastname: Walker
authors.affiliation: MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.
authors.forename: Sibu
authors.initials: S
authors.lastname: Varghese
authors.affiliation: MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.
authors.forename: Theodore
authors.initials: T
authors.lastname: Evan
authors.affiliation: MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.
authors.forename: Pierre S
authors.initials: PS
authors.lastname: Lao-Sirieix
authors.affiliation: Department of Histopathology, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: O'Donovan
authors.affiliation: Department of Histopathology, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Shalini
authors.initials: S
authors.lastname: Malhotra
authors.affiliation: University College London Hospital, London, UK.
authors.forename: Marco
authors.initials: M
authors.lastname: Novelli
authors.affiliation: Royal Victoria Infirmary, Newcastle upon Tyne, UK.
authors.forename: Babett
authors.initials: B
authors.lastname: Disep
authors.affiliation: NIHR Nottingham Digestive Disease Biomedical Research Unit, Queens Medical Centre, Nottingham University Hospital NHS Trust, Nottingham, UK.
authors.forename: Phillip V
authors.initials: PV
authors.lastname: Kaye
authors.affiliation: University College London Hospital, London, UK.
authors.forename: Laurence B
authors.initials: LB
authors.lastname: Lovat
authors.affiliation: University College London Hospital, London, UK.
authors.forename: Rehan
authors.initials: R
authors.lastname: Haidry
authors.affiliation: Royal Victoria Infirmary, Newcastle upon Tyne, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Griffin
authors.affiliation: NIHR Nottingham Digestive Disease Biomedical Research Unit, Queens Medical Centre, Nottingham University Hospital NHS Trust, Nottingham, UK.
authors.forename: Krish
authors.initials: K
authors.lastname: Ragunath
authors.affiliation: Queen Alexandra Hospital, Portsmouth, UK.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Bhandari
authors.affiliation: Saint Mark's Hospital, London, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Haycock
authors.affiliation: East and North Hertfordshire NHS Trust, QEII and Lister Hospitals, Stevenage, UK.
authors.forename: Danielle
authors.initials: D
authors.lastname: Morris
authors.affiliation: Northern Region Endoscopy Group, UK; North Tyneside General Hospital, North Shields, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Attwood
authors.affiliation: Northern Region Endoscopy Group, UK; County Durham and Darlington NHS Foundation Trust, Durham, UK.
authors.forename: Anjan
authors.initials: A
authors.lastname: Dhar
authors.affiliation: Northern Region Endoscopy Group, UK; South Tyneside NHS Foundation Trust, Tyne and Wear, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Rees
authors.affiliation: Northern Region Endoscopy Group, UK; North Tees and Hartlepool NHS Foundation Trust, Hartlepool, UK.
authors.forename: Matt D
authors.initials: MD
authors.lastname: Rutter
authors.affiliation: UK Cancer Prevention Trials Unit, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Ostler
authors.affiliation: UK Cancer Prevention Trials Unit, London, UK.
authors.forename: Benoit
authors.initials: B
authors.lastname: Aigret
authors.affiliation: UK Cancer Prevention Trials Unit, London, UK.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Sasieni
authors.affiliation: MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK. Electronic address: rcf29@MRC-CU.cam.ac.uk.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fitzgerald
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D000368:Aged; D001471:Barrett Esophagus / Q000175:diagnosis* / Q000473:pathology; D015415:Biomarkers / Q000032:analysis; D016022:Case-Control Studies; D003581:Cytodiagnosis / Q000379:methods*; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000473:pathology; D004945:Esophagoscopy; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D018570:Risk Assessment / Q000379:methods*
chemical_list: D015415:Biomarkers