Journal Article

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

Castle, John, Heah, Jing Y. E., Landberg, Göran, Pritchard, Susan A., Nicholson, Sarah L., Shaker, Hudhaifah, Bundred, Nigel J., Kirwan, Cliona C., Albadry, Harith, Harries, Lauren J.

2020

Overview

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. In a large prospective cohort study (n = 324) of breast cancer patients, increased expression of markers of coagulation (Tissue Factor, thrombin and their respective receptors PAR2 and PAR1) are localized to fibroblasts, increased in aggressive breast cancer subtypes, and correlate with reduced overall survival. The phenotypic change in fibroblasts to a procoagulant state occurs at the preinvasive (DCIS) stage, implying an epithelial‐stromal communication across the basement membrane in DCIS creates a procoagulant stromal milieu and potentially an environment to facilitate invasion.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Adult / Aged / Aged, 80 and over / Angiogenesis / Anticoagulants / Antithrombin / Breast - cytology / Breast - pathology / Breast - surgery / Breast cancer / Breast Neoplasms - mortality / Breast Neoplasms - pathology / Breast Neoplasms - surgery / Cancer and Oncology / Cancer och onkologi / Cancer-Associated Fibroblasts - metabolism / Carcinoma, Ductal, Breast - mortality / Carcinoma, Ductal, Breast - pathology / Carcinoma, Ductal, Breast - surgery / Carcinoma, Intraductal, Noninfiltrating - mortality / Carcinoma, Intraductal, Noninfiltrating - pathology / Carcinoma, Intraductal, Noninfiltrating - surgery / Clinical Cancer Research / Clotting / coagulation / DCIS / Disease-Free Survival / ErbB-2 protein / Female / fibroblast / Fibroblasts / Follow-Up Studies / Gene expression / Gene Expression Profiling / Humans / Invasiveness / Lymphatic system / Mastectomy / Medical prognosis / Middle Aged / Multivariate analysis / Neoplasm Invasiveness - pathology / Original Research / PAR1 / PAR2 / Phenotypes / Prognosis / Prospective Studies / Stroma / Therapeutic applications / Thrombin / Thrombin - metabolism / Thromboplastin - metabolism / thrombosis / Tissue Array Analysis / Tissue factor / Tumor Microenvironment / Variables / Variance analysis / Wound healing / Young Adult