Abstract 652: Non-invasive biomarker potential of quantifying the pro-peptides of type XI collagen alpha 1 chain (PRO-C11) in patients with pancreas cancer

Abstract

Abstract Introduction: Pancreas cancer (PC) is one of the most stroma-rich cancers with up to 80% of the tumor mass being stroma. Consequently, PC is a highly resistant disease. Cancer-associated fibroblasts (CAFs) and the collagens they produce are major components of the PC stroma. The fibrillar fibroblast-derived type XI collagen has been suggested to be a specific CAF marker and quantifying type XI collagen synthesis could have biomarker potential in PC. Therefore, we developed two competitive enzyme-linked immunosorbent assays (ELISAs) targeting the pro-peptide of type XI collagen and validated them both in patients with PC. Methods: Two ELISAs were developed and technically validated based on monoclonal antibodies raised against type XI collagen at either the cleavage site A'253↓ (PRO-C11-253) or A'511↓ (PRO-C11-511). Levels of PRO-C11-253 and PRO-C11-511 were measured in a discovery cohort in serum samples from patients with PC (n = 40, stage I-IV), chronic pancreatitis (CP) (n = 12) and healthy controls (n = 20). Any biomarker potential from the discovery cohort was validated in pretreatment serum from 686 patients with PC (validation cohort, stage I-IV). Biomarker levels were evaluated for the association with stage and with overall survival (OS) by univariate and multivariate cox regression analysis adjusting for various clinical risk factors such as performance status, stage, liver metastasis and CA19-9. Results: PRO-C11-511 was significantly upregulated in PC and CP compared to healthy controls whereas no difference was seen with PRO-C11-253. Likewise, there was no association between levels of PRO-C11-253 and OS (HR (95% CI): 1.00 (0.42-2.35), p = 0.9958), whereas high levels of PRO-C11-511 (> 75 percentile) were significantly associated with poor OS (HR (95% CI): 3.33 (1.44-7.69), p = 0.0045). In the validation cohort, PRO-C11-511 was upregulated in late stages compared to early stages (stage IV vs. stage II: p = 0.0004, stage IV vs. stage III: p = 0.0101). Furthermore, high levels of PRO-C11-511 (> 75 percentile) were associated with poor OS (HR (95% CI): 1.68 (1.40-2.02), p < 0.0001) and remained significant after adjusting for the clinical risk factors (HR (95% CI): 1.41 (1.13-1.74), p = 0.0021). Conclusion: Quantifying pretreatment serum levels of pro-peptides of type XI collagen (PRO-C11-511) predicts poor OS in patients with PC. This was not the case for PRO-C11-253 highlighting that the processing of type XI collagen pro-peptides is important from a biomarker perspective. Thus, targeting specific epitopes can be highly disease specific. PRO-C11-511 that indirectly quantifies CAF activity, should be validated in future studies to expand on the clinical applicability as a predictive and monitoring biomarker. Citation Format: Neel Ingemann Nissen, Stephanie Kehlet, Astrid Z. Johansen, Inna M. Chen, Morten Karsdal, Julia S. Johansen, Hadi M. Diab, Lars N. Jørgensen, Nicholas Willumsen. Non-invasive biomarker potential of quantifying the pro-peptides of type XI collagen alpha 1 chain (PRO-C11) in patients with pancreas cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 652.