Abstract
PurposeCirculating tumour cells (CTCs) are a marker of poor prognosis and are associated with increased risk of venous thromboembolism in metastatic breast cancer (MBC). We aimed to determine if the presence of CTCs and plasma markers of hypercoagulability [thrombin–antithrombin III (TAT), fibrinogen and d-dimer] are biomarkers of survival in MBC.Methods/patientsIn a prospective study of MBC patients, CTC (CellSearch®) enumeration and plasma TAT, fibrinogen and d-dimer measured prior to commencement of treatment for disease progression were correlated to overall survival.ResultsAt study completion, of 50 MBC patients recruited (median age 59 years, range 36–82), 40 patients had died (median survival 417 days, range 58–2141). CTCs (≥ 1/7.5 ml) were identified in 16 patients (median number of cells per 7.5 ml, 3 (range 1–31) and were associated with systemic hypercoagulability (medians TAT: 8.1 vs. 5.2 ng/ml, p = 0.03; fibrinogen: 4.3 vs. 3.1 g/l, p = 0.03; d-dimer: 1327 vs. 683 ng/ml, p = 0.0001). At 1 year, of 16 patients with ≥ 1 CTC, 7 had died (44%), compared to 5 of 26 (19%) patients in the no-CTC group. The presence of ≥ 1 CTC was associated with a trend for reduced overall survival (median 455 days vs. 614 days, p = 0.15). Plasma TAT inversely correlated with survival and was significantly higher in patients dying within 1 year (median 9.8 vs. 5.2 ng/ml, p = 0.004) whilst d-dimer showed a trend for reduced 1-year survival (median 1211 vs. 817 ng/ml, p = 0.06). MBC patients with combined high d-dimer (≥ 895 ng/ml) and CTC positivity (≥ 1/7.5 ml whole peripheral blood) had significantly reduced survival (p = 0.04).ConclusionsThe correlation between CTCs, hypercoagulability and reduced survival in MBC suggests the coagulation system supports tumour cell metastasis and is, therefore, a potential therapeutic target.
Highlights
Venous thromboembolism (VTE) in cancer is common and a major cause of death
The trend for reduced overall survival in MBC patients with ≥ 1 Circulating tumour cells (CTCs)/7.5 ml whole blood is consistent with previous reports [30, 31]
The very significant association between plasma Thrombin–antithrombin III (TAT) and overall survival supports previous work from our team demonstrating higher concentrations of TAT in metastatic compared to early breast cancer patients or age-matched female controls [6]
Summary
Venous thromboembolism (VTE) in cancer is common and a major cause of death. Breast cancer is associated with a three- to fourfold increased risk of venous thromboembolism (VTE) compared to age-matched women without cancer [1, 2]. Half of all cancer patients and 90% of metastatic patients exhibit coagulation abnormalities. This is reflected in activation of the clotting cascade [6], platelet activation [7] and alterations of fibrinolytic activity [8] resulting in clinical and biochemical evidence of coagulation [9, 10]. Plasma TAT and d-dimer are higher in early-breast cancer patients than in healthy controls [12]. D-dimer (a product of fibrin degradation and the end product of coagulation activation) is increased in breast cancer, with raised levels being found in 58% of patients with involved lymph nodes, and only 8% of patients without lymph node disease [10] Circulating fibrinogen, which is converted to fibrin by thrombin, has showed utility in distinguishing breast cancer from benign breast disease [13], and increases with disease progression [14]. d-dimer (a product of fibrin degradation and the end product of coagulation activation) is increased in breast cancer, with raised levels being found in 58% of patients with involved lymph nodes, and only 8% of patients without lymph node disease [10]
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