Thrombin Generation and D-Dimer for Prediction of Disease Progression and Mortality in Patients with Metastatic Gastrointestinal Cancer

Abstract

Background: the tight and reciprocal interaction between cancer and hemostasis has stimulated investigations on the possible role of hemostatic biomarkers in predicting specific cancer outcomes, such as disease progression (DP) and overall survival (OS). In a prospective cohort of newly diagnosed metastatic gastrointestinal (GI) cancer patients from the HYPERCAN study, we aimed to assess whether the hemostatic biomarker levels measured before starting any anticancer therapy may specifically predict for 6-months DP (6m-DP) and for 1-year OS (1y OS). Methods: plasma samples were collected and tested for thrombin generation (TG) as global hemostatic assay, and for D-dimer, fibrinogen, and prothrombin fragment 1 + 2 as hypercoagulation biomarkers. DP and mortality were monitored during follow-up. Results: A prospective cohort of 462 colorectal and 164 gastric cancer patients was available for analysis. After 6 months, DP occurred in 148 patients, providing a cumulative incidence of 24.8% (21.4−28.4). D-dimer and TG endogenous thrombin potential (ETP) were identified as independent risk factors for 6m-DP by multivariate Fine−Gray proportional hazard regression model corrected for age, cancer site, and >1 metastatic site. After 1 year, we observed an OS of 75.7% (71.9−79.0). Multivariate Cox regression analysis corrected for age, site of cancer, and performance status identified D-dimer and ETP as independent risk factors for 1y OS. Patients with one or both hemostatic parameters above the dichotomizing threshold were at higher risk for both 6m-DP and 1-year mortality. Conclusion.: in newly diagnosed metastatic GI cancer patients, pretreatment ETP and D-dimer appear promising candidate biomarkers for predicting 6m-DP and 1y OS. In this setting, for the first time, the role of TG as a prognostic biomarker emerges in a large prospective cohort.

Keywords: D-dimer; gastrointestinal cancer; hypercoagulability; prognosis; survival; thrombin generation.

Figure 1

(A) Crude cumulative incidence of 6m-DP and (B) Kaplan–Meier estimates of 1-year OS according to risk groups based on D-dimer and TG ETP levels. Continuous line = low risk (both under threshold), dashed line = intermediate risk (at least one over threshold), and dotted line = high risk (both over threshold). Grey lines are corresponding estimates of the competing event. 6m-DP: 6-month disease progression, 1y OS: 1-year overall survival, TG: thrombin generation, ETP: endogenous thrombin potential.