High turnover of extracellular matrix reflected by specific protein fragments measured in serum is associated with poor outcomes in two metastatic breast cancer cohorts. Issue 11 (29th September 2018)

• Record Type: Journal Article
• Authors: Lipton, Allan; Leitzel, Kim; Ali, Suhail M.; Polimera, Hyma V.; Nagabhairu, Vinod; Marks, Eric; Richardson, Angelique E.; Krecko, Laura; Ali, Ayesha; Koestler, Wolfgang; Esteva, Francisco J.; Leeming, Diana J.; Karsdal, Morten A.; Willumsen, Nicholas
• Is Part Of: International journal of cancer. Volume 143:Issue 11(2018)
• Page Start: 3027
• Page End: 3034
• Publication Date: 2018-09-29
• Subjects: breast cancer -- outcome -- stroma -- extracellular matrix -- biomarkers -- serum; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.31627
• Languages: English
• ISSNs: 0020-7136

Abstract

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. Abstract : What's new? Increased extracellular matrix (ECM) formation and matrix metalloprotease‐mediated ECM degradation contribute to tumorigenesis and generate specific collagen fragments that are released into circulation. Here, the authors demonstrate the potential of measuring such ECM remodeling biomarkers for clinical application in the metastatic breast cancer (MBC) setting. They found that high levels of ECM remodeling biomarkers in pre‐treatment serum were associated with poor outcomes in two independent MBC cohorts receiving systemic therapy. The findings support that ECM remodeling is an important mechanism in breast cancer pathogenesis, and that serum quantification of ECM remodeling holds promise for prognostic and/or predictive purposes in MBC.