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- Shaker, H., et al.
(author)
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Breast cancer stromal clotting activation (Tissue Factor and thrombin): A pre-invasive phenomena that is prognostic in invasion
- 2020
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In: Cancer Medicine. - : Wiley. - 2045-7634. ; 9:5, s. 1768-1778
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Journal article (peer-reviewed)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 (≥3.2ng/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. © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
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