Fibrinogen and D-Dimer Predict Venous Thromboembolism (VTE) in a Prospective Observational Cohort of Metastatic Breast Cancer Patients

Introduction: Breast cancer is the most prevalent malignancy among women worldwide and is the cancer type in which the thrombogenic effect of anti-cancer drugs was first recognized (Levine et al, NEJM 1988). The occurrence of VTE in patients with metastatic breast cancer upon commencing anticancer treatment significantly affects disease burden, quality of life, and healthcare expenditure. Consequently, it is essential to accurately discern patients with a significant risk of developing thrombosis, thereby warranting medical prophylaxis. However, the stratification of outpatients on chemotherapy for metastatic breast cancer initiating an anticancer treatment by validated risk assessment models (RAMs) remains an unmet clinical need.

In a prospective, observational cohort study of newly diagnosed metastatic breast cancer patients beginning chemotherapy, we aim to evaluate the incidence of VTE and the role of hypercoagulation biomarkers in predicting VTE and mortality within a 12-month follow-up.

Methods: Newly diagnosed, metastatic breast cancer patients were enrolled and prospectively followed for VTE and mortality (HYPERCAN study, ClinicalTrials.gov ID#NCT02622815). Blood samples were collected at enrolment, before starting chemotherapy, and tested for biomarkers of blood clotting activation (i.e. D-dimer, fibrinogen, prothrombin-fragment 1+2 [F1+2]). Univariable and multivariable analyses were performed using the Cox proportional hazard model to identify statistically significant prognostic factors (SPSS Statistics, version 21.0). Fine and Gray competing risk analysis was also performed (Stata Corp, version 16).

Results: A prospective cohort of 189 metastatic breast cancer patients with a median age of 59 years (range 32-91 years) was analyzed. Ductal carcinoma was diagnosed in 80% of patients. The most represented molecular subtypes were Luminal B HER2-neg (32.3%) > Luminal B HER2-pos (24.3%) > Luminal A (13.2%) > triple negative (TN, 9.5%) > HER2-pos (9%). Within 1 year of enrollment, 13 patients experienced VTE in a median time of 173 days (IQR: 52-258), resulting in a VTE cumulative incidence of 7.0% (95% CI 3.7-11.5). During the same follow-up period, the cumulative incidence of mortality was 12% (95% CI 7.4-17), within a median time to death of 212 days (IQR 106-306). Patients who experienced VTE had significantly higher baseline levels of D-dimer and fibrinogen than those who remained VTE-free during the same follow-up period (p<0.02). No significant differences were found in F1+2 levels between the two groups. In the Fine and Gray competing univariable analysis, D-dimer [HR 1.02 (95% CI 1.00-1.04), p=0.008] and Fibrinogen (HR 1.06 (95% CI 1.03-1.10), p<0.001), considered as continuous variables, emerged as significant predictors of VTE. Following correction for clinical variables (age, BMI, cardiovascular risk factors, and tumor histological characteristics), both biomarkers retained their independent associations with VTE occurrence.

To establish specific cut-off values for each biomarker, D-dimer and fibrinogen levels were categorized into quartiles based on their distribution within the cohort. The results showed that D-dimer values greater than 533 ng/mL (2nd quartile) [HR 3.8 (95% CI 1.7 – 8.7), p=0.032] or fibrinogen values exceeding 428 mg/dL (3rd quartile) [HR 2.6 (95% CI 1.03–6.4), p=0.042] were significantly associated with an increased risk of VTE. Subsequently, the patients were categorized into two risk groups based on whether their biomarker values were above or below the identified thresholds. Specifically, analysis using Kaplan-Meier curves based on the D-dimer threshold revealed a VTE incidence of 3.3% versus 11% (p=0.029) in the low- and high-risk groups, respectively. Similarly, stratification by the fibrinogen threshold demonstrated a VTE incidence of 3.0% versus 18% (p<0.001) in the low- and high-risk groups. In this cohort, the occurrence of VTE did not affect the mortality rate, which was 64% in patients with VTE versus 51% in patients with no VTE (p=ns).

Conclusion: Our data indicated that pre-chemotherapy D-dimer and fibrinogen levels are effective in identifying metastatic breast cancer patients at higher risk of VTE. These findings highlight the potential of these biomarkers in enhancing risk stratification and guiding personalized treatment strategies for breast cancer patients.