Abstract 140: Profiling ECM biomarkers PRO-C3 and PRO-C5 in plasma from patients with esophagogastric cancer

Abstract Background: Esophagogastric cancer encompasses malignancies of the esophagus, esophagogastric junction, and stomach. These cancers involve distinct regions of the esophagus and gastroesophageal junction (GEJ) and exhibit unique clinicopathologic, histologic, and mutational features. The major constituents of the tumor microenvironment (TME) are besides the tumor cells themselves, cancer associated fibroblasts (CAFs), stromal cells and the extracellular matrix (ECM). CAFs synthesize excess amounts of collagens leading to a fibrotic TME with poor response to anti-cancer treatment; it was previously found that among other types of collagens COL3A1 and COL5A1 are expressed in most of activated CAFs. The aim of this study was to investigate the relevance of non-invasive serological biomarkers of type III collagen synthesis (PRO-C3) and type V collagen synthesis (PRO-C5) in patients with GEAC and ESCC. Methods: Levels of PRO-C3 and PRO-C5 were measured non-invasively using competitive enzyme-linked immunosorbent assays in EDTA Plasma from patients diagnosed with esophageal squamous cell carcinoma (ESCC) (n=27), gastroesophageal adenocarcinoma (GEAC) (n=165) and compared to healthy controls (n=20). Blood samples were obtained during biopsy, and the biomarker measurements reflect baseline levels. PRO-C3 and PRO-C5 levels in patients with GEAC and ESCC were assessed according to disease stage, treatment type and resection status. Results: Circulating PRO-C3 levels were significantly elevated in both GEAC (p = 0.0025) and ESCC (p = 0.0022), while PRO-C5 levels were markedly increased in both subtypes (GEAC: p = 0.0012; ESCC: p = 0.0002). PRO-C5 levels were higher in ESCC compared to GEAC (p = 0.0023), whereas PRO-C3 levels were similar between the two (p = 0.441). Stratifying by treatment intention showed no significant differences in PRO-C3 or PRO-C5 levels in ESCC patients receiving curative or palliative care. In GEAC, PRO-C5 levels were higher in palliative treatment patients (p = 0.01). For resection status, neither PRO-C3 nor PRO-C5 levels varied significantly in GEAC. In ESCC, PRO-C3 levels were elevated in non-resected samples (p = 0.002). Stratification by cancer stage revealed significant increases in PRO-C5 levels in GEAC patients at Stage III (p = 0.002) and Stage IV (p = 0.004). Conclusion: The non-invasive fibrosis-associated biomarkers PRO-C3 and PRO-C5, indicative of type III and type V collagen synthesis mediated by activated CAFs, are elevated in patients with ESCC and GEAC. These biomarkers show promise as non-invasive tools for stratifying and monitoring patients across different subtypes of esophagogastric cancer. Citation Format: Eleonora Moroncini, Andrea Ponzetta, Magnus Nilsson, Fredrik Klevebro, Rebecca Maltez de Sousa, Nora Norén, Morten Karsdal, Nicholas Willumsen. Profiling ECM biomarkers PRO-C3 and PRO-C5 in plasma from patients with esophagogastric cancer [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 140.