Today’s Mistakes and Tomorrow’s Wisdom in Development and Use of Biomarkers for Barrett’s Esophagus

Abstract

Background: A histological diagnosis of dysplasia is our current best predictor of progression in Barrett’s esophagus (BE), the precursor of esophageal adenocarcinoma (EAC). Despite periodic endoscopic surveillance and assessment of dysplastic changes, we fail to identify the majority of those who progress before the development of EAC, whereas the majority of patients undergo endoscopy without showing progression. Summary: Low-grade dysplasia (LGD), confirmed by expert pathologists, identifies BE patients at higher risk for progression, but the diagnosis of LGD is challenging. Recent research indicates that progression from BE to EAC is heterogeneous and can accelerate via genome doubling and genome catastrophes, resulting in different ways to progression. We identified 3 target areas, which may help to overcome the current lack of an accurate biomarker: (1) the implementation of somatic point mutations, chromosomal alterations, and epigenetic changes (genomics and epigenomics), (2) evaluate and develop biomarkers over space and time, (3) use new sampling methods such as noninvasive self-expandable sponges and endoscopic brushes. This review focus on the state of the art in risk stratifying BE and on recent advances which may overcome the limitations of current strategies. Key Messages: A panel of clinical factors, genomics, epigenomics, and/or proteomics will most likely lead to an assay that accurately risk stratifies BE patients into low- or high-risk for progression. This biomarker panel needs to be developed and validated in large cohorts containing a sufficient number of progressors, with testing samples over space (spatial distribution) and time (temporal distribution). For implementation in clinical practice, the technique should be affordable and applicable to formalin-fixed paraffin-embedded samples, which represent standard of care.

Promises and Limitations of Current Models for Understanding Barrett’s Esophagus and Esophageal Adenocarcinoma

“…Although patient-derived samples are needed for identification of new biomarkers, experimental models are also necessary to study the functional significance of these biomarkers, for which complex human cell culture models are particularly relevant. 129 …”

Barrett’s Esophagus: Today’s Mistakes and Tomorrow’s Wisdom

“…Currently, a histological diagnosis of dysplasia is the best predictor of progression in Barrett's esophagus. However, as Frei et al [7] describe in Chapter 3, progression of nondysplastic Barrett's esophagus to esophageal adenocarcinoma is heterogenous and can accelerate via genome doubling and genome catastrophes, resulting in different ways of progression. The use of biomarkers may therefore lead to more accurate risk stratification of Bar-rett's patients into low or high risk for progression.…”