The breast cancer coagulome in the tumor microenvironment and its role in prognosis and treatment response to chemotherapy

Background The procoagulant phenotype in cancer is linked to thrombosis, cancer progression and immune response. It remains to identify novel treatment that reduces both the risk of thrombosis and cancer progression, without excess bleeding risk. Objectives Here, we aimed to broadly investigate the breast tumor coagulome and its relation to prognosis, treatment response to chemotherapy, and the tumor microenvironment. Methods Key coagulation related genes (n=35) were studied in a Norwegian cohort with tumor (n=134) and normal (n=189) tissue and in the cancer genome atlas (TCGA) (n=1052) dataset. We performed gene set variation analysis (GSVA) in the Norwegian cohort, and in the TCGA cohort associations with the tumor microenvironment and prognosis were evaluated in addition. Analyses with cBioPortal, ESTIMATE, TIMER, TISIDB, TISCH and ROC plotter were used. Six independent breast cancer cohorts were used to study the tumor coagulome and treatment response to chemotherapy. Results 22 differentially expressed coagulation related genes were identified in breast tumors. Several coagulome factors were correlated with tumor microenvironment characteristics and were expressed by non-malignant cells in the tumor microenvironment. PLAT and F8 were independent predictors of better overall survival and progression-free survival, respectively. F12 and PLAU were predictors of worse progression-free survival. The PROCR-THBD-PLAT signature showed a promising predictive value (AUC=0.75; 95% CI 0.69-0.81, P=3.6x10-17) for combination chemotherapy with fluorouracil-epirubicin-cyclophosphamide (FEC). Conclusions The breast tumor coagulome showed potential in prediction of prognosis and chemotherapy response. Cells within the tumor microenvironment are sources of coagulome factors and may serve as therapeutic targets of coagulation factors.