Abstract 2020: Fibroblast derived type III collagen pro-peptides (PRO-C3) in plasma is associated with outcome for patients with NSCLC treated with anti-PD1 plus chemotherapy

Abstract Background: Tumor fibrosis is essential for defining outcome of patients with various solid tumors including lung cancer. The associated cancer associated fibroblasts (CAFs) activation and increased deposition of type III collagen leads to immune exclusion and high interstitial pressure in the tumor microenvironment. Recently, the USA FDA issued a Letter of Support to encourage use of the non-invasive fibrosis biomarker PRO-C3 (type III collagen pro-peptides) in patients with solid tumors (https://www.fda.gov/media/169332/download). Here we investigate PRO-C3 as a prognostic biomarker in patients with non-small cell lung cancer (NSCLC). Methods: First, we investigated the PRO-C3 production (measured by ELISA) and total collagen deposition (Sirius red staining) in primary lung CAFs activated with TGF-beta, by use of the validated scar-in-a-jar in vitro model. Second, we measured PRO-C3 in pre-treatment plasma samples from 40 patients with stage IIIa to IVb NSCLC. Patients were treated with Pembrolizumab (anti-PD1) plus platinum-doublet chemotherapy (carboplatin, cisplatin, pemetrexed, or paclitaxel). PRO-C3 was correlated to overall survival outcome (OS) by Kaplan Meier analysis and Cox regression analysis after allocating patients into PRO-C3 subgroups (below/above the median of 51.5 ng/mL). Results: PRO-C3 was produced by lung CAFs after activation with TGF-beta in vitro and PRO-C3 correlated to increased net-collagen deposition. Among the 40 patients with NSCLC, the median follow-up was 13.2 months. Patients with high PRO-C3 had a median OS of 9.0 months compared to 31.5 months in patients with low PRO-C3 (log-rank p-value=0.0023). In support, patients with high PRO-C3 had a Hazard Ratio (HR) for OS of 3.8 (95%CI: 1.5-9.7, p=0.004). Conclusions: Type III collagen pro-peptides (PRO-C3) was produced by activated lung CAFs and is a surrogate of fibrogenesis. High PRO-C3 levels in pre-treatment plasma was associated with poor outcome for patients with NSCLC treated with anti-PD1 plus chemotherapy. These data suggest that quantifying tumor fibrosis is important for prognostication of patients with lung cancer. Citation Format: Nicholas Willumsen, Lola Lecru, Thibaut Brugat, John Stagg, Bertrand Routy, Morten A. Karsdal. Fibroblast derived type III collagen pro-peptides (PRO-C3) in plasma is associated with outcome for patients with NSCLC treated with anti-PD1 plus chemotherapy [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 2020.