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. 2025 Feb 12;120(6):1285-1295.
doi: 10.14309/ajg.0000000000003367.

Spatiotemporal Study of a Risk-Stratification Epigenetic-Based Biomarker Assay in Patients With Barrett Esophagus

Sarah E Laun  1 , Lisa Kann  1 , Jerome Braun  1 , Francia Pierre  1 , Suji Kim  1 , Stacey Gilbert  1 , Daniel Lunz  1 , Andrew Kalra  2   3 , Ke Ma  2   4 , Yulan Cheng  2 , Cadman L Leggett  5 , Ali H Zaidi  6 , Ashten N Omstead  6 , Louis Korman  7 , Blair Jobe  6   8 , Lorrie Perpetua  9 , Bruce D Greenwald  10 , Tara Maddala  1 , Stephen J Meltzer  2   11
Affiliations

Spatiotemporal Study of a Risk-Stratification Epigenetic-Based Biomarker Assay in Patients With Barrett Esophagus

Sarah E Laun et al. Am J Gastroenterol. .

Abstract

Introduction: Barrett esophagus (BE) is the strongest known risk factor for developing esophageal adenocarcinoma (EAC), the second-most lethal cancer in the United States. Esopredict is a novel validated methylation-based biomarker assay that provides precise quantification of neoplastic progression risk in BE patients. Inherit challenges, including tissue heterogeneity, sampling error, interobserver variability, and inconsistent adherence to surveillance biopsy guidelines, may affect the predictive value results of Esopredict obtained at different anatomic locations or different sampling time points.

Methods: To investigate the spatiotemporal performance of Esopredict across multiple spatiotemporal sampling points, we profiled 220 biopsies obtained from 58 BE patients, including 11 patients with overlapping spatial and temporal biopsies. We focused on spatial profiling (i.e., multiple biopsies obtained at several anatomic locations during a single endoscopy) and temporal profiling (i.e., biopsies obtained from multiple endoscopies performed at different time points). Each patient had an initial histologic diagnosis of nondysplastic Barrett esophagus, indefinite for dysplasia, or low-grade dysplasia. Final follow-up (endpoint) biopsies showed either high-grade dysplasia or EAC (progressors), or nondysplastic Barrett esophagus, indefinite for dysplasia, or low-grade dysplasia (nonprogressors). Biopsies were analyzed with Esopredict to compute a progression risk score, which quantified the likelihood of future progression to high-grade dysplasia or EAC within 5 years.

Results: In 52 spatially profiled patients, Esopredict demonstrated a sensitivity of 81% (17/21 progressor patients), based on the highest-scoring biopsy from each patient; sensitivity increased to 100% (12/12) when end point biopsies occurred within 5 years of the index (initial) biopsy. In 28 temporally profiled patients, sensitivity was 100% (8/8 patients), based on the biopsy performed at the time point closest to the end point biopsy.

Discussion: Esopredict showed high predictive performance in multiple spatiotemporal samples in BE patients. These data further support the use of Esopredict as a robust test to distinguish high-risk BE patients, who may benefit from endoscopic eradication therapy or increased surveillance frequency, from low-risk patients, who may be candidates for less frequent surveillance and noninterventional observation.

Keywords: biopsy assay; clinical decisions; epigenetics; esophageal adenocarcinoma; personomics; predictive biomarkers; prognostic assay.

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Conflict of interest statement

Guarantor of the article: Stephen J. Meltzer, MD.

Specific author contributions: S.E.L. designed and conducted the study; provided administrative, technical, and material support; acquired, analyzed, and interpreted the data; drafted, reviewed, and revised the manuscript, and approved the final draft submitted. L.K. and D.L. designed and conducted the study; provided administrative, technical, and material support; analyzed and interpreted the data; reviewed and revised the manuscript, and approved the final draft submitted. S.E.L., and J.B. analyzed and interpreted the data; drafted, reviewed, and revised the manuscript, and approved the final draft submitted. S.G. and A.K. reviewed and revised the manuscript and approved the final draft that was submitted. F.P., S.K. acquired and analyzed data; reviewed the manuscript, and approved the final draft submitted. K.M. and Y.C. provided material support, reviewed the manuscript, and approved the final draft submitted. C.L.L., B.D.G., A.H.Z., A.N.O., L.K. provided material support; T.M., S.J.M. provided guidance for the study's design; supervised the study; provided administrative, technical, and material support; interpreted the data; reviewed and revised the manuscript; and approved the final draft submitted.

Financial support: Support from the following grants: R44DK136424, R41CA261376, R01DK118250, R01CA287294.

Potential competing interests: S.E. Laun, D.G. Lunz, and L. Kann are paid employees, equity holders of Previse, and inventors of the patented technologies described. S.J. Meltzer is an equity holder of Previse and an inventor of the patented technologies described. Y. Chen is an inventor of the patented technologies described. K. Ma is an equity holder of Previse. S. Gilbert and F. Pierre are paid employees and equity holders of Previse. T. Maddala and J. Braun are paid consultants of Previse. A.K., C.L., B.G., A.Z., L.K. have no conflicts of interest to disclose in relation to this research.

Figures

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Graphical abstract
Figure 1.
Figure 1.
Risk stratification of Esopredict and consort diagram for spatiotemporal study. (a) Esopredict risk stratification based on previous publication (24). (b) Breakdown of spatial and temporal patients and the biopsies for each. A total of 58 patients and 220 biopsies were assayed with Esopredict, including 11 patients who had overlapping biopsies that met both criteria for spatial and temporal cohorts. Index biopsies are the earliest known biopsy, and outcome biopsies are the last known biopsy. Follow-up biopsies are in between index and outcome. BE, Barrett esophagus; EAC, esophageal adenocarcinoma; HGD, high-grade dysplasia; IND, indefinite for dysplasia; LGD, low-grade dysplasia; ND, nondysplastic.
Figure 2.
Figure 2.
Esopredict risk scores of spatial profiling patients with index biopsies of NDBE. Patients with index (initial) biopsies that were ND, who then progressed to HGD or EAC within 5 years. The x-axis shows each patient (n = 7) had between 2 and 4 spatial biopsies with segment length noted when available (short < 3 cm, long > 3 cm). The y-axis shows the Esopredict score to predict progression within 5 years. The line at the risk score of 26 designates the lower risk (low and low-moderate) from the higher risk (high-moderate and high) scores (red background). BE, Barrett esophagus; EAC, esophageal adenocarcinoma; HGD, high-grade dysplasia; ND, nondysplastic.
Figure 3.
Figure 3.
Esopredict risk score of temporal profiling patients with index biopsies of NDBE. (a) Patients with index (initial) biopsies that were ND who then progressed to HGD or EAC (progressors). Each x-axis shows each biopsy interval in years before the outcome biopsy (time 0). Each y-axis shows the risk score to predict progression within 5 years. The line at 26 designates the lower risk (low and low-moderate) from the higher risk (high-moderate and high) scores (red background). Note: Yellow highlighted data points represent Esopredict scores in biopsies outside the 5-year prediction. (b) Patients with index (initial) biopsies that were ND who then remained ND (nonprogressors). Each x-axis shows each biopsy interval in years before the outcome biopsy (time 0). Each y-axis shows the risk score to predict progression within 5 years. The line at 26 designates the lower risk (low and low-moderate) from the higher risk (high-moderate and high) scores (red background). Note: Yellow highlighted data points represent Esopredict scores in biopsies outside the 5-year prediction. HGD, high-grade dysplasia; EAC, esophageal adenocarcinoma; LGD, low-grade dysplasia; ND, nondysplastic; NP, nonprogressor patients.
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