Blood‐based tumor fibrosis markers as diagnostic and prognostic biomarkers in patients with biliary tract cancer. Issue 5 (1st December 2022)

• Record Type: Journal Article
• Authors: Christensen, Troels D.; Jensen, Christina; Larsen, Ole; Leerhøy, Bonna; Hansen, Carsten P.; Madsen, Kasper; Høgdall, Dan; Karsdal, Morten A.; Chen, Inna M.; Nielsen, Dorte; Johansen, Julia S.; Willumsen, Nicholas
• Is Part Of: International journal of cancer. Volume 152:Issue 5(2023)
• Page Start: 1036
• Page End: 1049
• Publication Date: 2022-12-01
• Subjects: biliary tract cancer -- collagen turnover -- extracellular matrix biomarkers -- prognosis -- tumor fibrosis; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.34356
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract: Biliary tract cancer (BTC) is characterized by a desmoplastic extracellular matrix (ECM). We tested the diagnostic and prognostic use of seven circulating biomarkers of ECM remodeling: pro‐peptides of type III collagen (PRO‐C3), VI (PRO‐C6) and XI (PRO‐C11), matrix metalloprotease (MMP) degraded type III collagen (C3M) and type IV collagen (C4M) fragments, granzyme B degraded type IV collagen fragments (C4G) and MMP degraded and citrullinated vimentin (VICM) a marker of macrophage activation. The study included 269 patients with all stages of BTC and 49 patients with benign biliary tract diseases. Serum samples from BTC patients were collected before surgery, or before first‐ or second‐line chemotherapy. C3M, C4M, PRO‐C3, PRO‐C6, PRO‐C11 and VICM levels were elevated in patients with BTC compared to patients with benign disease. Receiver operating characteristics curve analyses identified PRO‐C3 (area under curve [AUC] = 0.87) as the ECM marker with the best diagnostic performance. The ECM biomarkers correlated with inflammation biomarkers (C‐reactive protein [CRP], interleukin‐6 [IL‐6] and YKL‐40) but not with CA19‐9. To investigate prognostic performance, patients were split into three cohorts (first‐line, second‐line and surgery). Elevated ECM biomarker levels were associated with short overall survival (OS), but only pretreatment PRO‐C3 and PRO‐C6 were associated with OS in both the first‐line and second‐line settings when adjusting for CA19‐9, performance status and stage in a multivariate Cox‐regression analyses. Our results indicate that collagen remodeling is increased in patients with BTC and associated with survival. The collagen pro‐peptides (PRO‐C3 and PRO‐C6) could be used as novel biomarkers in these patients. Abstract : What's new? Biliary tract cancer is characterized by a desmoplastic stroma, but the potential use of blood‐based fibrosis markers in these patients has been little investigated. Here, the authors found that circulating biomarkers related to turnover of type III, type IV, type VI and type XI collagen and macrophage activation were increased in patients with biliary tract cancer compared to controls. Increased serum levels of biomarkers related to turnover of type III, IV and VI collagens were associated with short patient survival. Our study links biliary tract cancer and fibrosis and is the first to identify PRO‐C3 as a potential diagnostic biomarker.