A Tissue Systems Pathology Test Outperforms the Standard-of-Care Variables in Predicting Progression in Patients With Barrett's Esophagus

Abstract

Introduction: Objective risk stratification is needed for patients with Barrett's esophagus (BE) to enable risk-aligned management to improve health outcomes. This study evaluated the predictive performance of a tissue systems pathology [TSP-9] test (TissueCypher) vs current clinicopathologic variables in a multicenter cohort of patients with BE.

Methods: Data from 699 patients with BE from 5 published studies on the TSP-9 test were evaluated. Five hundred nine patients did not progress during surveillance, 40 were diagnosed with high-grade dysplasia/esophageal adenocarcinoma (HGD/EAC) within 12 months, and 150 progressed to HGD/EAC after 12 months. Age, sex, segment length, hiatal hernia, original and expert pathology review diagnoses, and TSP-9 risk classes were collected. The predictive performance of clinicopathologic variables and the TSP-9 test was compared, and the TSP-9 test was evaluated in clinically relevant patient subsets.

Results: The sensitivity of the TSP-9 test in detecting progressors was 62.3% compared with 28.3% for expert-confirmed low-grade dysplasia (LGD), while the original diagnosis abstracted from medical records did not provide any significant risk stratification. The TSP-9 test identified 57% of progressors with nondysplastic Barrett's esophagus (NDBE) ( P < 0.0001). Patients with NDBE who scored TSP-9 high risk progressed at a similar rate (3.2%/yr) to patients with expert-confirmed LGD (3.7%/yr). The TSP-9 test provided significant risk stratification in clinically low-risk patients (NDBE, female, short-segment BE) and clinically high-risk patients (IND/LGD, male, long-segment BE) ( P < 0.0001 for comparison of high-risk classes vs low-risk classes).

Discussion: The TSP-9 test predicts risk of progression to HGD/EAC independently of current clinicopathologic variables in patients with BE. The test provides objective risk stratification results that may guide management decisions to improve health outcomes for patients with BE.

Graphical abstract

Figure 1.

TissueCypher (TSP-9) provides significantly improved risk stratification vs pathology diagnoses. Kaplan-Meier (KM) analysis of probability of progression to HGD/EAC in patients with BE stratified into the following: (a) low-risk, intermediate-risk, and high-risk classes by the TSP-9 test; (b) NDBE, IND, and LGD subsets by the original/real-world diagnoses abstracted from health records; (c) NDBE, IND, and LGD by expert review diagnoses provided as part of research studies. (d) Multivariable analysis comparing prediction of progression by the TSP-9 test vs expert review diagnosis. n = 699 patients with BE in panels a–d, including 150 incident progressors, 40 patients with prevalent HGD/EAC, and 509 nonprogressors. Five-year hazard ratios (HRs) with a 95% confidence interval (CI) were calculated from an accelerated failure time (AFT) regression model. EAC, esophageal adenocarcinoma; HGD, high-grade dysplasia; IND, indefinite for dysplasia; LGD, low-grade dysplasia; NDBE, nondysplastic Barrett's esophagus.

Figure 2.

TissueCypher (TSP-9) test predicts incident progression and detects the presence of missed prevalent HGD/EAC. (a) Kaplan-Meier (KM) analysis of probability of progression to HGD/EAC in nonprogressors (n = 509) and incident progressors (n = 150) stratified into low-risk, intermediate-risk, and high-risk classes by the TSP-9 test. (b) Box and whisker plots of the TSP-9 risk score in nonprogressors (n = 509) and patients with prevalent HGD/EAC (n = 40). (c) Prevalence-adjusted probability of progression to HGD/EAC within 5 years as a continuous function of the TSP-9 risk score in all 699 patients. Dashed curves indicate a 95% confidence interval (CI). EAC, esophageal adenocarcinoma; HGD, high-grade dysplasia.

Figure 3.

TissueCypher (TSP-9) provides significant risk stratification in diagnostic subsets of NDBE and IND/LGD. Kaplan-Meier (KM) analysis of probability of progression to HGD/EAC in patients stratified into low-risk, intermediate-risk, and high-risk classes by the TSP-9 test in the following subsets of patients with: (a) real-world pathology diagnosis of NDBE (n = 290 nonprogressors, 91 incident progressors, and 11 patients with prevalent HGD/EAC); (b) Real-world pathology diagnosis of IND/LGD (n = 219 nonprogressors, 59 incident progressors, and 29 patients with prevalent HGD/EAC); (c) Expert review diagnosis of NDBE (n = 438 nonprogressors, 110 incident progressors, and 19 patients with prevalent HGD/EAC); (D) Expert review diagnosis of IND/LGD (n = 71 nonprogressors, 40 incident progressors, and 21 patients with prevalent HGD/EAC). Five-year hazard ratios (HRs) with a 95% confidence interval (CI) were calculated from an accelerated failure time (AFT) regression model. EAC, esophageal adenocarcinoma; HGD, high-grade dysplasia; IND, indefinite for dysplasia; LGD, low-grade dysplasia; NDBE, nondysplastic Barrett's esophagus.

Figure 4.

TissueCypher (TSP-9) provides significant risk stratification in subsets of male, female, short-segment, and long-segment BE patients. Kaplan-Meier (KM) analysis of probability of progression to HGD/EAC in patients stratified into low-risk, intermediate-risk, and high-risk classes by the TSP-9 test in the following patient subsets: (a) Female patients (n = 124 nonprogressors, 21 incident progressors, and 5 patients with prevalent HGD/EAC); (b) Male patients (n = 385 nonprogressors, 129 incident progressors, and 35 patients with prevalent HGD/EAC); (c) Short-segment BE (n = 148 nonprogressors, 27 incident progressors, and 9 patients with prevalent HGD/EAC); (d) Long-segment BE (n = 311 nonprogressors, 121 incident progressors, and 27 patients with prevalent HGD/EAC). Five-year hazard ratios (HRs) with a 95% confidence interval (CI) were calculated from an accelerated failure time (AFT) regression model. EAC, esophageal adenocarcinoma; HGD, high-grade dysplasia.