A Thrombotic Biomarker-Based Risk Assessment Scoring Model for Disease Recurrence in Breast Cancer Patient Candidate to Systemic Chemotherapy
Authors: Falanga Anna , Giaccherini Cinzia , Marchetti Marina , Masci Giovanna , Verzeroli Cristina , Russo Laura , Celio Luigi , Sarmiento Roberta , Gamba Sara , Tartari Carmen J , Diani Erika , Vignoli Alfonso , Malighetti Paolo , Spinelli Daniele , Tondini Carlo , Barni Sandro , Giuliani Francesco , Petrelli Fausto , D'Alessio Andrea , Gasparini Giampietro , De Braud Filippo , Santoro Armando , Labianca Roberto 
Published: November 2019

Background. Hypercoagulability, a common finding in cancer patients, is associated with an increased risk of both thrombosis and tumor development. The HYPERCAN study (ClinicalTrials.gov, ID# NCT02622815) is an ongoing Italian prospective, multicenter, observational study, evaluating the predictive value of thrombotic markers for early cancer diagnosis in healthy subjects and for cancer prognosis and venous thromboembolism in patients with newly diagnosed malignant disease. In this analysis of a large cohort of patients with breast cancer, we evaluated whether pre-chemotherapy thrombotic biomarker levels: 1. are associated with breast cancer-specific clinicopathological features; and 2. may predict for disease recurrence (DR).
Patients and Methods. D-dimer, fibrinogen, prothrombin fragment 1+2 (F1+2), and FVIIa/antithrombin complex (FVIIa/AT) 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 DR were identified by Cox-regression multivariate analysis and used for generating a risk assessment model. The study protocol is approved by the local Ethics Committee. Informed written consent is obtained from all study subjects.
Results. Increased pre-chemotherapy D-dimer, fibrinogen, and F1+2 levels were significantly associated with a large tumor size (≥ 5 cm) and lymph node positivity. After 3.4 years follow-up, 71 patients experienced a DR. Comparison of the levels of the hypercoagulation variables of patients who experienced relapse versus patients who remained disease-free during follow-up showed that there were no statistical differences for all, but F1+2 biomarker levels, which were significantly higher in the group patients who relapsed [223 (115-618) vs 197 (115-385) pmol/l; p=0.024]. In addition, correlation analyses showed that pre-chemotherapy levels of fibrinogen were significantly and inversely associated with time to relapse (β = -0.317; p=0.012). Cox-multivariate analysis identified F1+2 (HR 2; 95% CI, 1.1-3.6; p=0.019), tumor size ≥ 5cm (HR 2.6; 95% CI, 1.4-4.6; p=0.001), and Luminal B HER2-neg or TN molecular subtypes (HR 3.9; 95% CI, 2.1-7.5; p<0.001) as independent risk factors for DR. Based on these variables, we generated a risk assessment model that significantly identified patients at low- versus high-risk of DR (cumulative incidence: 6.2 vs 20.7%; HR=3.5; p<0.001).
Conclusion. Our prospective laboratory data from the HYPERCAN breast cancer subjects were essential for generating a scoring model for DR risk assessment. Future investigations addressing the role of plasma thrombotic biomarkers in breast cancer patients' management are warranted and may provide the rationale for development of new therapeutic strategies.
Project funded by AIRC "5xMILLE Multiunit extension program" n. 12237 grant from the "Italian Association for Cancer Research (AIRC)".

Disclosures
Santoro: Bayer: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; BMS: Consultancy; Sandoz: Speakers Bureau; Eisai: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; Lilly: Speakers Bureau; Celgene: Speakers Bureau; Servier: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Roche: Speakers Bureau; Abb-Vie: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Arqule: Consultancy, Speakers Bureau; MSD: Speakers Bureau; Takeda: Speakers Bureau; BMS: Speakers Bureau.