Thrombin generation predicts early recurrence in breast cancer patients

Abstract

Background Cancer patients present with a hypercoagulable state often associated with poor disease prognosis. Objectives This study aims to evaluate whether thrombin generation (TG), a global coagulation test, may be a useful tool to improve the identification of patients at high risk of early disease recurrence (ie, E‐DR within 2 years) after breast cancer surgery. Patients/Methods A cohort of 522 newly diagnosed patients with surgically resected high‐risk breast cancer were enrolled in the ongoing prospective HYPERCAN study. TG potential was measured in plasma samples collected before starting systemic chemotherapy. Significant predictive hemostatic and clinic‐pathological parameters were identified in the derivation cohort by Cox regression analysis. A risk prognostic score for E‐DR was generated in the derivation and tested in the validation cohort. Results After a median observation period of 3.4 years, DR occurred in 51 patients, 28 of whom were E‐DR. E‐DR subjects presented with the highest TG values as compared to both late‐DR (from 2 to 5 years) and no relapse subjects (P < .01). Multivariate analysis in the derivation cohort identified TG, mastectomy, triple negative and Luminal B HER2‐neg molecular subtypes as significant independent predictors for E‐DR, which were utilized to generate a risk assessment score. In the derivation and validation cohorts, E‐DR rates were 2.3% and 0% in the low‐risk, 10.1% and 6.3% in the intermediate‐risk, and 18.2% and 16.7%, in the high‐risk categories, respectively. Conclusions Inclusion of TG in a risk‐assessment model for E‐DR significantly helps the identification of operated breast cancer patients at high risk of very early relapse.

Validation of the Role of Thrombin Generation Potential by a Fully Automated System in the Identification of Breast Cancer Patients at High Risk of Disease Recurrence

“…42 The role of TG parameters as prognostic biomarkers in breast cancer has been previously demonstrated in a casecontrol study where a decrease of lag time and ttP and an increase of peak value predicted the presence of breast cancer. 39 Recently, our group identified and internally validate the role of ETP when included in a risk assessment model for DR. 16 To confirm the relevance of our previous observation, prechemotherapy parameters of TG by ST Genesia were tested in relation to E-DR. Despite the low absolute differences and the large confidence intervals, the comparison of TG parameters between E-DR and DF patients showed significantly elevated ETP and peak values compared with DF subjects, with no differences in ETP and peak inhibition by TM.…”

“…Similar results were obtained in our previous study, in which TG measurement was performed by CT assay where patients displayed higher ETP and peak values compared with healthy controls. 16 The differences in ETP and peak values between patients and controls were 6.4 and 17%, respectively, in the absence of TM; the presence of TM magnified these differences that became equal to 40% for both ETP and peak values. The calculation of ETP and peak inhibition by TM, based on values obtained in the presence and absence of TM, provides an estimate of PC anticoagulant pathway function.…”

“…According to the HYPERCAN main study proposal, we performed a series of prechemotherapy evaluation of different hemostatic biomarkers that allowed us to identify and internally validate a risk assessment model of E-DR based on ETP obtained with the CT assay. 16 However, partial automation, lack of reagent standardization, and clinical validation limit the use of CT assay in the clinical practice, 20 and this prompted us to reevaluate in this cohort patients, the role of ETP by performing the TG analysis by the fully automatized ST Genesia system. In this re-evaluation, we also included the study of the anticoagulant C pathway by the same system with dedicated reagents to further explore the hypercoagulable profile of these patients.…”

“…17 Particularly, in our previous study, among the different TG parameters, the endogenous thrombin potential (ETP), defined as the net amount of thrombin that plasma can generate, was successfully integrated in a prediction risk assessment model, ameliorating the identification of subjects at higher risk of early relapse (i.e., within 2 years). 16 TG by the CAT assay is well reproducible within a single laboratory when standardized preanalytical and analytical conditions for measurement are applied. [18][19][20] However, partial automation, lack of reagent standardization, and clinical validation limit the use of CAT assay in the clinical practice.…”

“…15 Recently, in the frame of the HYPERCAN study, we could demonstrate in a cohort of high-risk breast cancer patients with surgically removed tumor and candidate to receive adjuvant chemotherapy, a crucial role of thrombin generation (TG) performed by the calibrated automated thrombography (CAT) in identifying subjects at high risk of disease relapse. 16 The CAT is a global hemostatic assay that represents an in vitro test that evaluates the capacity of an individual to generate thrombin resulted from the relative strength of the pro-and anticoagulant drivers. TG can detect coagulation factor deficiencies; it is sensitive to anticoagu-lant drugs and to prothrombotic states such as deficiency of antithrombin, protein C (PC), or protein S as well as to hyperprothrombinemia and resistance to activated PC.…”