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Commentary on: The Utility of Biomarkers for Risk Stratification in Barrett’s Esophagus

The narrative review in this issue of Foregut by Drs. Konda and Ashton summarizes the rapidly developing literature on biomarkers for risk stratification of Barrett’s esophagus (BE). These biomarkers have the potential to solve several key challenges in current clinical management. The most commonly-faced challenge is the risk stratification of non-dysplastic BE (NDBE), where a low rate of progression over a broad population of patients1,2 makes balancing the risks, benefits, and costs of endoscopic and histologic surveillance difficult. An accurate biomarker might allow for selection of patients in whom further surveillance is not warranted. Once a decision for surveillance has been made in NDBE, indeterminate for dysplasia, or low-grade dysplasia, biomarkers could further serve to enhance the accuracy of surveillance, identifying those patients with prevalent dysplasia missed by forceps biopsies. For patients with confirmed low-grade dysplasia, biomarkers are needed to discriminate between the need for endoscopic eradication therapy and endoscopic surveillance.3 Beyond these potential major applications, biomarkers could aid management in a variety of other settings, including post-ablation surveillance, or when used in conjunction with non-endoscopic screening or surveillance. Given the plethora of biomarkers described in the piece by Drs. Konda and Ashton, some dating back to the 1990s, why have more not made their way into clinical practice? There are well-described systematic barriers in translating research into clinical practice. First is inertia. Investigators have suggested that the mean time from a translational breakthrough to its clinical application is 17 years.4 Specific barriers have variably been present as well. The need to manage fresh tissue versus samples preserved in formalin, the use of sample collection by methods or devices not routinely used, and the costs of trained laboratory staff, equipment, and reagents to perform a biomarker may all act as barriers to clinical adoption. Insurance companies may resist the advance due to additional cost. Some of the challenge for clinicians to understand a biomarker’s value stems from limitations in the current literature. Studying biomarkers in BE is hard. The natural history of BE, and particularly NDBE, with its low rate of progression to adenocarcinoma, mean that the rate of progression in the average NDBE population is small. Therefore, very large populations studied over long time periods are required for robust statistical estimates. As a consequence, well-powered prospective cohort studies or randomized controlled trials of biomarkers are very expensive and may not be feasible. Most progress in the literature has depended on cross-sectional studies, casecontrol studies, and retrospective cohort studies. While expedient, these studies have a higher risk of bias compared to more rigorous designs. Many studies are from convenience samples from tertiary care centers that may not accurately represent the population in which the biomarker would be applied.5 Few current studies have external validation cohorts, and many lack internal validation methods, which suggests they may over-promise with regard to their prediction metrics.6 To overcome these challenges and increase the likelihood of clinical use, creative approaches are required. Combining biomarker investigations with large prospective clinical studies designed for other reasons (for instance ablation trials, chemoprevention studies, etc.) can mitigate costs. This approach is especially attractive when the parent study has a control or standard-of-care arm, allowing assessment of the biomarker in what is essentially current practice. Studying the method of biomarker collection is also important. Pathology samples have been shown to sample as little as 5% of mucosa surface, whereas tools like Cytosponge7 and wide area transepithelial sampling brushing8 sample the mucosa more broadly. However, gains in accuracy of biomarker(s) due to field effects and more global sampling must be demonstrated, to justify the additional time and expense necessary to apply the additional means of collection. Currently, some biomarkers are coupled with and being tested in only 1 tissue collection system. It may be that a biomarker being tested only in forceps biopsies is most efficacious in brush samplings, or that a biomarker being tested on non-endoscopic sponges might work best with wide-area transepithelial sampling. If we do not broaden our approach, we risk missing the most accurate combination. Finally, future biomarker studies must take into account the totality of what we know regarding risk stratification, so as not to over-sell the value of the assay. For instance, a biomarker might predict a 2-fold risk of progression in NDBE. However, if most of that increased risk could have been predicted based on other demographic and disease-specific factors already available at the time of using the biomarker (eg, such as smoking 997232 GUTXXX10.1177/2634516121997232ForegutCotton and Shaheen article-commentary2021