Abstract 7509: Path-Omics: Elevated plasma cell infiltration into aneuploid epithelium predicts Barrett’s esphagus progression to adenocarcinoma

Abstract Background: Barrett’s esophagus (BE) is a precancerous condition characterized by the metaplastic replacement of esophageal epithelium in response to gastroesophageal reflux. Although the progression rate to invasive carcinoma is low, identifying high-risk patients remains a critical unmet need, especially as BE prevalence rises. While molecular and immune microenvironment changes associated with BE progression are documented (Nowicki-Osuch 2021), there is a gap in reliable pathology-level indicators to assess cancer risk. This study aims to uncover cancer-relevant changes in BE using computational pathology approaches. Methods: We analyzed a unique dataset comprising 742 esophageal biopsy slides from 138 patients, and with DNA content abnormalities, including aneuploid (n=125 slides from 26 patients), determined by flow cytometry. Clinical follow-up data for cancer progression was available for 117 of these patients. Using computational pathology models, we trained a multiple-instance learning framework for aneuploid prediction (Lu 2021, Ercan 2024) on 45 slides, and a single-cell detection model based on the ACformer architecture (Huang 2023), fine-tuned on 13, 343 cells. Spatial immune cell distribution within the epithelium was quantified using the Morisita-Horn index (MHI), which measures spatial overlap between immune cells and BE cells. Results: The MIL-based aneuploid prediction model achieved a balanced accuracy of 74.3% and an AUC of 0.81 on the test set (n= 388), while the single-cell detection & classification model reached accuracies of 73.7% for detection and 98.3% for classification (in epithelium, lymphocyte, plasma cell, eosinophil, neutrophil and stromal cell classes). Immune cell MHI was significantly elevated in aneuploid biopsies (p < 10e-4, n=125). Aneuploid was found to strongly correlate with cancer progression (p < 10e-5, n=33). In aneuploid samples, immune cell infiltration analysis revealed that increased immune cell abundance and higher plasma cell MHI scores were significantly associated (p < 10e-4, < 10e-4, respectively) with cancer progression in the vicinity of aneuploid BE epithelium, consistent with the observations in (MK Strasser 2023). Conclusion: This study demonstrates the potential of Patho-Omic tools to predict aneuploid in BE biopsies and identify cancer progression-associated features directly from routine pathology slides. By combining slide-level aneuploid prediction with single-cell detection, we highlight the role of immune cell spatial dynamics in cancer progression. These findings lay the groundwork for stratifying BE patients by progression risk through biopsy image analysis. Citation Format: Caner Ercan, Xiaoxi Pan, Thomas G. Paulson, Matthew D. Stachler, Carlo C. Maley, Yinyin Yuan. Path-Omics: Elevated plasma cell infiltration into aneuploid epithelium predicts Barrett’s esphagus progression to adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7509.