Baseline Hemostatic Biomarker Assessment Identifies Breast Cancer Patients at High Risk for Venous Thromboembolism During Chemotherapy

Abstract

(1) Background: The presence of metastatic disease significantly increases the risk of venous thromboembolism (VTE) in breast cancer, particularly during chemotherapy. Although not categorized as a highly thrombogenic malignancy, the elevated global prevalence of this cancer places a substantial number of patients at risk of thrombosis, which cannot yet be accurately predicted by validated risk assessment models (RAMs), highlighting the need for a dedicated model. (2) Aim: This study aims to develop a RAM for VTE in newly diagnosed metastatic breast cancer patients enrolled in a prospective, observational, and multicenter study. (3) Methods: A cohort of 189 patients beginning antitumor therapy were enrolled and prospectively monitored for VTE and mortality. Blood samples collected at enrollment were tested for D-dimer, fibrinogen, FVIII, prothrombin fragment 1 + 2 (F1 + 2), and thrombin generation (TG). Competing risk analyses were performed to identify significant predictors. (4) Results: Within one year, the cumulative incidences of VTE and mortality were 7.0% and 12%, respectively. Univariable analysis identified high Ki-67, D-dimer, FVIII, fibrinogen, and TG levels, along with low hemoglobin levels, as independent predictors of VTE. Only Ki-67, fibrinogen, FVIII, and hemoglobin were retained as significant predictors in multivariable analysis. These variables were further examined by multiple linear regression, which revealed Ki-67 and fibrinogen as the most significant parameters. A continuous RAM was then developed based on Ki-67 and fibrinogen (c-statistics 0.78), categorizing patients into low-risk and high-risk groups for VTE (2% vs. 13%; SHR 3.6, p = 0.018). This stratification could not be achieved using currently validated models for VTE risk. (5) Conclusions: We developed an accurate RAM for VTE that enables the identification of metastatic breast cancer patients at high risk for VTE, which supports clinicians in personalized thromboprophylaxis strategies if externally validated.

Keywords: D-dimer; Ki-67; fibrinogen; hemostatic biomarkers; hypercoagulability; metastatic breast cancer; mortality; venous thromboembolism.

Figure 1

Distribution of hemostatic biomarkers according to the development of VTE within 1 year, and VTE-free. (A) Factor VIII; (B) fibrinogen; (C) D-dimer; (D) prothrombin fragment 1 + 2 (F1 + 2). In the box plots, the median is shown by the line inside the box, and the whiskers indicate the interquartile range of the values; dots represent values over the 95th percentile.

Figure 2

Distribution of thrombin generation parameters according to 1-year VTE and VTE-free patients. (A) Lag time; (B) time to peak; (C) peak of thrombin generation; (D) endogenous thrombin potential. In the box plots, the median is shown by the line inside the box, and the whiskers indicate the interquartile range of the values; dots represent values over the 95th percentile.

Figure 3

Receiver operating characteristic (ROC) curve of the model and cumulative incidence of venous thromboembolism (VTE) within 1 year. (A) Accuracy of the model by ROC curve; (B) Kaplan–Meier of the cumulative incidence of VTE at 1-year of follow-up. The dotted red line represents the high-risk group, and the blue line represents the low-risk group.