The Tissue Systems Pathology Test Predicts Risk of Progression in Medicare-Eligible Patients with Barrett's Esophagus

Introduction: Accurate prediction of risk of progression to esophageal adenocarcinoma (EAC) is needed in patients with Barrett’s esophagus (BE), which disproportionately affects patients ≥ 65 years of age (Medicare-eligible), representing the majority of EAC cases diagnosed each year in the U.S. Multiple studies have validated that the tissue systems pathology (TSP-9) test predicts risk of neoplastic progression in patients with BE. This study evaluated the performance of TSP-9 for predicting risk of progression to high-grade dysplasia (HGD) or EAC in Medicare-eligible BE patients. Methods: A pooled analysis was performed on data from 5 studies of 290 BE patients who were ≥ 65 years old with known outcomes, including 84 patients who progressed to HGD/EAC in 2.4 years (median; IQR 1.3 - 3.5). Data were also analyzed from a second cohort on clinical use of the TSP-9 test ordered by 356 physicians at 251 clinical sites for 2,078 BE patients ≥ 65 years old. The risk stratification performance of TSP-9 results and clinicopathologic variables was evaluated. Results: In the pooled analysis of patients with known outcomes, TSP-9 demonstrated significantly higher sensitivity (64.0%; 95% CI 53.3 - 74.7) than expert pathology and real-world pathology (22.6%; 95% CI 13.3 - 33.3 and 38.7%; 95% CI 28.0 - 49.3, respectively; P < 0.05) in detecting patients who progressed to HGD/EAC. In multivariable analyses with clinicopathologic variables, TSP-9 was the strongest, independent predictor of progression to HGD/EAC (HR 7.2; 95% CI 4.2 - 14.2; P < 0.0001; Table 1, Figure 1A). In the clinical use cohort, TSP-9 provided significant risk stratification in all evaluated subsets, identifying 17.7% of patients as high/intermediate risk for progression to HGD/EAC (Figure 1B-E). Patients with NDBE who scored TSP-9 high risk had a higher 5-year progression risk (16.6%; IQR 13.7 - 25.0) than patients with LGD (6.1%; IQR 3.0 - 14.5; Figure 1B). Conclusion: The TSP-9 test risk-stratifies BE patients ≥ 65 years old independently of clinicopathologic variables and has significantly higher sensitivity for detection of progressors than pathology diagnosis of LGD. In clinical use, the TSP-9 test identified a high-risk subset of NDBE patients who had a higher progression risk than patients with LGD, enabling early detection of patients requiring escalation of care to reduce the incidence of EAC. TSP-9 provides clinically impactful risk prediction in patients ≥ 65 years old to guide risk-aligned care for improved health outcomes.Figure 1.: TSP-9 provides significant risk stratification in BE patients ≥65 years old. A: Kaplan-Meier analysis of TSP-9 risk classes for 290 patients with BE (NDBE, n = 160; IND, n = 27; and LGD, n = 103), including 84 patients who progressed to HGD/EAC within 2.4 years (median; IQR, 1.3–3.5) and 206 patients with a median follow-up of 6.1 years (IQR, 4.7–7.7) with no disease progression. B: The 5-year probability of progression to HGD/EAC predicted by TSP-9 in clinical use in 2,078 patients with NDBE (n = 1,862), IND (n = 104), or LGD (n = 77). C: Risk stratification by TSP-9 in clinical use for patients with NDBE (n = 1,862), IND (n = 104), or LGD (n = 77); female (n = 765) and male (n = 1,313) BE patients; and patients with short- (n = 67) or long-segment (n = 64) BE. TSP-9, Tissue Systems Pathology-9 test; BE, Barrett's esophagus; Int, intermediate; NDBE, non-dysplastic Barrett’s esophagus; IND, indefinite for dysplasia; LGD, low-grade dysplasia. Table 1. - Multivariable Analysis Comparing Clinicopathologic Variables and TSP-9 Test Results for Predicting Risk of Progression to HGD/EAC in Medicare-Eligible BE Patients within 5 Years Variable HR (95% CI) P Segment Length: Long vs Short 0.74 (0.4–1.4) 0.289 Hiatal Hernia: Present vs Absent 0.85 (0.5–1.7) 0.647 Age* 1.01 (1.0–1.1) 0.650 Sex: Male vs Female 2.21 (1.2–5.7) 0.030 Real-World Dx: IND vs NDBE 0.52 (0.0–1.5) 0.271 Real-World Dx: LGD vs NDBE 1.45 (0.8–2.7) 0.161 TSP-9: Intermediate vs Low Risk 1.73 (0.8–3.6) 0.139 TSP-9: High vs Low Risk 7.23 (4.2–14.2) < 0.0001 *For every year of age, risk of progression to HGD/EAC (age X HR). TSP-9, Tissue Systems Pathology-9; HGD/EAC, high-grade dysplasia/esophageal adenocarcinoma; BE, Barrett’s esophagus; HR, hazard ratio; CI, confidence interval; Dx, diagnosis; IND, indefinite for dysplasia; NDBE, non-dysplastic Barrett’s esophagus; LGD, low-grade dysplasia.