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Cancer Med. 2020 Jan 21. doi: 10.1002/cam4.2748. [Epub ahead of print]

Breast cancer stromal clotting activation (Tissue Factor and thrombin): A pre-invasive phenomena that is prognostic in invasion.

Author information

1
Faculty of Biology, Medicine and Health, Division of Cancer Sciences, School of Medical Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester, UK.
2
Department of Pathology, Institute for Biomedicine, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
3
Department of Histopathology, Manchester University NHS Foundation Trust, Wythenshawe, Manchester, UK.
4
Department of Histopathology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK.
5
Department of Histopathology, East Lancashire Hospitals NHS Trust, Blackburn, UK.
6
The Nightingale Centre and Prevent Breast Cancer Research Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK.

Abstract

BACKGROUND:

Tumor stroma, of which fibroblasts are the most abundant cell, resembles a non-healing wound, where a procoagulant environment creates a permissive milieu for cancer growth. We aimed to determine if tumor expression of coagulation factors (procoagulant phenotype), and systemic hypercoagulability, occur at the preinvasive (ductal carcinoma in situ; DCIS) stage and correlate with breast cancer subtype, disease-free survival (DFS), and overall survival (OS).

METHODS:

In a prospective cohort of early breast cancer (DCIS, n = 76; invasive, n = 248) tumor, normal breast and plasma were examined. Fibroblast and epithelial expression of Tissue Factor (TF), thrombin, PAR1, PAR2, and plasma thrombin-antithrombin (TAT) and D-dimer were correlated with clinicopathological data, and 5-year survival.

RESULTS:

Fibroblast expression of TF, thrombin, and PAR1 was increased in DCIS and invasive cancer compared to normal breast fibroblasts (P ≤ .003, all). Fibroblast TF, thrombin, PAR1, and PAR2 was increased in cancers with high Ki67, high grade, ER- (vs ER+), and HER2+ (vs HER2-) (all P < .05). On univariate analysis, fibroblast TF expression was inversely associated with DFS (P = .04) and OS (P = .02). D-dimer was higher in node positive (507 (CI: 411-625) ng/mL, n = 68) vs negative patients (428 (CI: 387-472) ng/mL, n = 171, P = .004) and inversely associated with OS (P = .047). On multivariate analysis, plasma TAT was associated with reduced OS (HR 3.26, CI 1.16-3.1, P = .02), with a high plasma TAT (≥3.2 ng/mL) associated with > 3-fold mortality risk compared to low TAT.

CONCLUSION:

This demonstrates procoagulant phenotypic changes occur in fibroblasts at the preinvasive stage. Fibroblast procoagulant phenotype is associated with aggressive breast cancer subtypes and reduced survival. Coagulation may be a therapeutic target in breast cancer.

KEYWORDS:

DCIS; PAR1; PAR2; breast cancer; coagulation; fibroblast; thrombin; thrombosis; tissue factor

PMID:
31962001
DOI:
10.1002/cam4.2748
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