Hemostatic Biomarkers and Venous Thromboembolism Are Associated With Mortality and Response to Chemotherapy in Patients With Pancreatic Cancer

Abstract

Objective: Pancreatic cancer activates coagulation and increases risk of venous thromboembolism (VTE). We aimed at characterizing the association of hemostatic biomarkers and VTE with mortality and chemotherapy response. Approach and Results: Pancreatic cancer patients (n=145) were included in a prospective, observational cohort study (CATS [Vienna Cancer and Thrombosis Study]). Hemostatic biomarkers (D-dimer, extracellular vesicle–tissue factor activity, prothrombin fragment 1+2, fibrinogen, factor VIII, PAI-1 [plasminogen activator inhibitor 1], sP-selectin [soluble P-selectin], thrombin generation assay) were measured at inclusion. The impact of VTE on overall survival/progression-free survival (OS/PFS) was evaluated by multistate modeling. The association of biomarkers with OS was analyzed by Cox-regression and with PFS and disease control rate in patients initiating palliative chemotherapy (n=95) by Cox-regression and logistic regression. Multivariable analysis included stage, grade, sex, age, performance status, VTE (time-dependent), vascular infiltration/compression, and tumor marker levels (carbohydrate-antigen 19-9, carcinoembryonic antigen). VTE occurrence was associated with shorter OS (transition hazard ratio, 3.40 [95% CI, 2.05–5.64]) and shorter PFS (transition hazard ratio, 2.10 [1.16–3.79]). Median post-VTE OS/PFS in months was 5.5 [2.2–6.5] and 3.0 [1.5–3.9], compared with 13.4 [9.7–16.6] and 7.5 [5.9–9.8] in patients without VTE (both P <0.001). D-dimer, extracellular vesicle–tissue factor activity, PAI-1, and sP-selectin were associated with increased mortality (hazard ratio per doubling, 1.27 [1.00–1.61]; 1.63 [1.14–2.36]; 1.25 [1.06–1.47]; 1.52 [1.05–2.20]). In patients initiating palliative chemotherapy, higher D-dimer predicted shorter PFS (hazard ratio per doubling, 1.27 [1.01–1.60]) and lower disease control rate (odds ratio per doubling, 0.59 [0.36–0.98]). Conclusions: VTE diagnosis is associated with shorter OS and PFS. Higher baseline levels of D-dimer, extracellular vesicle–tissue factor activity, PAI-1, and sP-selectin were independently prognostic for increased mortality, and D-dimer predicted response to palliative chemotherapy.

Histopathological Features of Cancer-Associated Venous Thromboembolism: Presence of Intrathrombus Cancer Cells and Prothrombotic Factors

“…40,41 Among patients with pancreatic cancer, patients with high levels of serum PAI-1 had poor prognosis, compared with those with lower levels. 3 In addition, human pancreatic cancerbearing mice had higher plasma levels of PAI-1 than control mice, and this was associated with venous thrombus weight. 9 However, expression of these factors in human cancer-associated VTE tissue remains unknown.…”

“…2 Among patients with pancreatic cancer, the median overall survival of patients estimated after VTE was 5.5 months, compared with 13.4 months in patients without VTE. 3 Primary organs and histological types of cancer likely affect the underlying mechanisms of cancer-associated VTE. 4–6 Cancer cells are associated with the development of VTE by local venous stasis and the release of various prothrombotic factors, such as mucin, TF (tissue factor), podoplanin, plasminogen activator inhibitor-1 (PAI-1), cytokines, and other procoagulant substances.…”

Hemostasis and cancer: Impact of haemostatic biomarkers for the prediction of clinical outcomes in patients with cancer

“…HR: 1.29 [95% CI 1.03–1.61]) and decreased DCR during treatment (adj. OR: 0.61 [0.38–0.99]) in the subgroup of patients initiating palliative chemotherapy after study inclusion ( n = 95) 81 …”

“…For example, levels of EV-TF have been repeatedly shown to have a prognostic utility specifically in patients with pancreatic cancer. 80,81 Further, levels of PAI-1 have recently been identified as cancer-type specific prothrombotic biomarker in patients with pancreatic cancer, which further seems to represent a strong and independent predictor of OS and therapy response in this setting. 26,81 Regarding the most promising therapeutic setting for potential clinical application of hemostatic biomarkers, several considerations…”

“…In a recent analysis of the same prospective observational cohort study, a comprehensive panel of hemostatic biomarkers was evaluated for its association with OS and response to palliative chemotherapy in with pancreatic cancer ( n = 145) 81 . Higher baseline levels of D‐dimer, EV‐TF, sP‐selectin, and PAI‐1 were identified as independent predictors of increased mortality, whereas no association was observed for levels of F1 + 2, fibrinogen, and parameters of the TGA.…”