Abstract 2210: Importance of fibrillar collagen quality, not quantity, for patients with solid tumors
Authors: Nissen Neel Ingemann , Johansen Astrid Z. , Chen Inna M. , Jensen Christina , Hansen Carsten Palnæs , Thorlacius-Ussing Jeppe , Karsdal Morten , Johansen Julia S. , Willumsen Nicholas 
Published: June 2023

Abstract
Background: Abnormal architectures of collagen fibers in the extracellular matrix (ECM) is directly related to cancer associated fibroblast (CAF) activity and subtype and are hallmarks of tumor fibrosis and key for determining prognosis and response to treatment in patients with solid tumors. Quantifiable tumor fibrosis biomarkers are needed for patient stratification and a non-invasive approach (liquid biopsy) is preferred in particular in the advanced setting. Type I collagen (COL1) and type V collagen (COL5) are two collagens responsible for the densely packed fibrils in the fibrotic tumor microenvironment. While COL1 is the most abundant collagen, COL5 is known for controlling collagen fibril size and orientation, and therefore fibrillar collagen quality. Increased fibrotic activity results in release of collagen pro-peptides into the bloodstream of patients with cancer. In this study, we first evaluated the clinical utility of non-invasive collagen based liquid biomarkers of COL1 and COL5 in patients with various solid tumors and subsequently evaluated prognostic utility in patients with pancreatic cancer (PC).
Methods: In a discovery cohort, pro-peptides of COL1 (PRO-C1) and COL5 (PRO-C5) were measured in serum from patients with various stages of bladder-, breast-, colorectal-, head and neck-, kidney-, lung-, melanoma-, pancreatic-, prostate-, and stomach cancer (n=220) and compared to healthy controls (n=33). Based on these results, the biomarker potential of PRO-C5 was validated further in 814 patients with PC from the BIOPAC cohort (n=15, 201, 164 and 434 for stage 1-4, respectively) including assessment for associations with overall survival (OS) analyzed by Kaplan-Meyer curves and Cox regression analysis, alone, and after adjusting for age, gender, BMI, diabetes, smoking, CA19-9, stage, no. of metastatic sites, performance status, and cachexia.
Results: PRO-C5, not PRO-C1, was significantly elevated in serum from all types of cancer patients compared to healthy controls (p&lt;0.05 - p&lt;0.0001). Levels of PRO-C5 were similar in patients from the BIOPAC cohort to those found in the discovery cohort. Furthermore, when dividing patients from the BIOPAC cohort into quartiles based on PRO-C5 levels (Q1-Q4) a stepwise decrease was detected in median OS time (log rank, p&lt;0.0001). Moreover, patients in the upper quartile of PRO-C5 (Q4) had 65% increased risk of dying compared to patients in Q1 (HR=1.65, 1.35-2.02, p&lt;0.0001) and this remained significant after adjusting for other common risk factors by multivariate analysis (HR=1.69, 1.30-2.20, p=0.0001).
Conclusion: Type V collagen (COL5) pro-peptides measured in serum (PRO-C5) is a promising pan-tumor fibrosis liquid biopsy with indications of independent prognostic value in patients with pancreatic cancer. In the future, this may provide means for serological subtyping of CAF subtypes which will aid in treating cancer patients.
Citation Format: Neel Ingemann Nissen, Astrid Z. Johansen, Inna M. Chen, Christina Jensen, Carsten Palnæs Hansen, Jeppe Thorlacius-Ussing, Morten Karsdal, Julia S. Johansen, Nicholas Willumsen. Importance of fibrillar collagen quality, not quantity, for patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2210.