Thrombotic biomarkers for risk prediction of malignant disease recurrence in patients with early stage breast cancer

Cinzia Giaccherini, Marina Marchetti, Giovanna Masci, Cristina Verzeroli, Laura Russo, Luigi Celio, Roberta Sarmiento, Sara Gamba, Carmen J Tartari, Erika Diani, Alfonso Vignoli, Paolo Malighetti, Daniele Spinelli, Carlo Tondini, Sandro Barni, Francesco Giuliani, Fausto Petrelli, Andrea D'Alessio, Giampietro Gasparini, Filippo De BraudArmando Santoro, Roberto Labianca, Anna Falanga

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Abstract

In cancer patients, hypercoagulability is a common finding and it has been associated to an increased risk of venous thromboembolisms, but also to tumor proliferation and progression. In this prospective study, in a large cohort of patients with breast cancer, we aimed to evaluate whether pre-chemotherapy abnormalities in hemostatic biomarkers levels: 1. are associated with breast cancer-specific clinicopathological features; and 2. can predict for disease recurrence. D-dimer, fibrinogen, prothrombin fragment 1+2, and FVIIa/antithrombin levels were measured in 701 early-stage resected breast cancer patients, candidate to adjuvant chemotherapy and prospectively enrolled in the HYPERCAN study. Significant prognostic parameters for disease recurrence were identified by Cox-regression multivariate analysis and used for generating a risk assessment model. Pre-chemotherapy D-dimer, fibrinogen, and prothrombin fragment 1+2 levels were significantly associated with tumor size and lymph node metastasis. After 3.4 years follow-up, 71 patients experienced a recurrence. Cox-multivariate analysis identified prothrombin fragment 1+2, tumor size, and Luminal B HER2-neg or triple negative molecular subtypes as independent risk factors for disease recurrence. Based on these variables, we generated a risk assessment model that significantly differentiated patients at low- and high-risk of recurrence (cumulative incidence: 6.2 vs 20.7%; HR=3.5; p<0.001). Our prospective clinical and laboratory data from the HYPERCAN study were crucial for generating a scoring model for disease recurrence risk assessment in resected breast cancer patients, candidate to systemic chemotherapy. This finding stimulates future investigations addressing the role of plasma prothrombin fragment 1+2 in breast cancer patients' management, and in providing the rationale for new therapeutic strategies.

Original languageEnglish
JournalHaematologica
DOIs
Publication statusE-pub ahead of print - Sep 26 2019

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Giaccherini, C., Marchetti, M., Masci, G., Verzeroli, C., Russo, L., Celio, L., Sarmiento, R., Gamba, S., Tartari, C. J., Diani, E., Vignoli, A., Malighetti, P., Spinelli, D., Tondini, C., Barni, S., Giuliani, F., Petrelli, F., D'Alessio, A., Gasparini, G., ... Falanga, A. (2019). Thrombotic biomarkers for risk prediction of malignant disease recurrence in patients with early stage breast cancer. Haematologica. https://doi.org/10.3324/haematol.2019.228981