High turnover of extracellular matrix reflected by specific protein fragments measured in serum is associated with poor outcomes in two metastatic breast cancer cohorts

Abstract

Increased extracellular matrix (ECM) formation and matrix metalloprotease (MMP)-mediated ECM degradation are parts of tumorgenesis and generates collagen fragments that are released into circulation. We evaluated the association of specific collagen fragments measured in serum with outcomes in two independent metastatic breast cancer (MBC) cohorts. ELISAs were used to measure C1M (MMP-generated type I collagen fragment), C3M (MMP-generated type III collagen fragment), C4M (MMP-generated type IV collagen fragment), and PRO-C3 (pro-peptide of type III collagen) in pretreatment serum from a phase 3 randomized clinical trial of second-line hormone therapy (HR+, n = 148), and a first-line trastuzumab-treated cohort (HER2+, n = 55). All sites of metastases were included. The collagen fragments were evaluated by Cox-regression analysis for their association with time-to-progression (TTP) and overall survival (OS). In the HR+ cohort, higher C1M and C3M levels (75th percentile cut-off) were associated with shorter TTP; all fragments were associated with shorter OS. In the HER2+ cohort, higher levels of all fragments were associated with shorter TTP; higher PRO-C3 was associated with shorter OS. In multivariate analysis of the HR+ trial for OS, higher levels of all fragments were significant for reduced OS when added separately (C1M HR = 2.1, p < 0.001; C3M HR = 1.8, p = 0.028; C4M HR = 1.8, p = 0.018; PRO-C3 HR = 1.8, p = 0.017); none other clinical covariates were significant. In conclusion, collagen fragments quantified in pretreatment serum was associated with shorter TTP and OS in two independent MBC cohorts receiving systemic therapy. If validated, quantification of ECM remodeling in serum has potential as prognostic and/or predictive biomarkers in MBC.

<p>Cross-Linked Multimeric Pro-Peptides of Type III Collagen (PC3X) in Hepatocellular Carcinoma – A Biomarker That Provides Additional Prognostic Value in AFP Positive Patients</p>

“…been associated with poor outcomes in breast cancer and malignant melanoma. 27,28 However, PRO-C3's role in HCC remains to be established. The PRO-C3 biomarker does not differentiate between single stranded or cross-linked N-terminal pro-peptides ( Figure 1).…”

“…Multivariate Cox proportional-hazards regression was used to assess the independent predictive value of PC3X and AFP adjusted for the above mentioned clinical variables. For statistical purposes, PC3X and PRO-C3 levels under the 75th percentile cut-point were used as a reference to calculate the HR for patients with levels above the 75th percentile, which was based on the data distribution and previous studies 27,28. AFP levels under 20 IU/mL were used as a reference to calculate the HR for patients with elevated AFP levels 32.…”

Serum Type XIX Collagen is Significantly Elevated in Non-Small Cell Lung Cancer: A Preliminary Study on Biomarker Potential

“…The most dominant proteins in the ECM are the collagens, of which there are 28 different types [7]. Our research group has previously demonstrated that collagens and other ECM proteins can be valuable as non-invasive biomarker tools in different cancer forms [8][9][10][11][12][13][14][15][16][17].…”

Clinical value of serum hyaluronan and propeptide of type III collagen in patients with pancreatic cancer

“…Although HA and collagen expression in the TME are considered prognostic biomarkers, there are no/few studies examining serum concentrations of HA and type III collagen in patients with PC. Previous studies conducted in other malignancies have shown a negative correlation between serum HA and outcome and serum collagen fragments and outcome . The aim of this biomarker study was to investigate the clinical utility of serum HA and propeptide of type III collagen (PRO‐C3) in patients with PC.…”

“…Previous studies conducted in other malignancies have shown a negative correlation between serum HA and outcome [40][41][42][43][44][45] and serum collagen fragments and outcome. 33,[46][47][48] The aim of this biomarker study was to investigate the clinical utility of serum HA and propeptide of type III collagen (PRO-C3) in patients with PC.…”