Coagulation/fibrinolysis and circulating tumor cells in patients with advanced breast cancer

Abstract

Purpose: To evaluate the relationship between circulating tumor cells (CTCs) and standard coagulation tests in both a discovery and a validation cohort of patients with advanced breast cancer.

Methods: In a retrospective (n = 77) and a prospective (n = 92) study of patients with progressive advanced breast cancer, CTC count, platelet number, fibrinogen level, D-dimers, prothrombin time, and activated partial thromboplastin time were measured. The association between these coagulation studies and CTC count was analyzed. The impact of these measurements on overall survival (OS) was assessed.

Results: In both cohorts, results were similar; absolute CTC count was significantly associated to D-dimer level and inversely with platelet count. In the prospective cohort, quantification of tumor-derived extracellular vesicles (tdEVs) was associated with CTC count, and with coagulation abnormalities (low platelet count and increased D-dimers). tdEVs did not add to CTC count in predicting changes in platelets or D-dimers. In multivariate analysis only CTC ≥ 5 CTC/7.5 mL, ER status, HER2 status and lines of chemotherapy were associated with OS. In patients with terminally metastatic breast cancer, very high CTC counts are prevalent.

Conclusion: A significant association exists between increasing CTC number and increased D-dimers and decreased platelet counts, suggesting a potential role for CTCs as a direct contributor of intravascular coagulation activation. In patients with advanced and progressive breast cancer, abnormalities in routine coagulation tests is the rule. In patients with terminally advanced breast cancer a "leukemic" phase with high CTC count is prevalent.

Keywords: Advanced breast cancer; Circulating tumor cells; D-dimers; Diffuse intravascular coagulation; Platelets; Tumor derived extracellular vesicles.

Fig. 1

CTC count distribution cohort 1

Fig. 2

A Overall SURVIVAL (days) in patients with MBC for those with < 5 CTCs per 7.5 mL of whole blood and those in the group with ≥ 5 CTCs in 7.5 mL of whole blood (n = 77). (log rank HR 2.826, p < 0.0001). B1 Relationship between the ln D-dimers (ng/mL) versus OS (days) (R² = 0.465, p < 0.0001). B2 Overall Survival (days) in Patients with MBC for those with < or > median D-dimer (n = 75). (log rank HR 2.586, p < 0.0001). C Relationship between ln CTC (x/7.5 mL) and ln D-dimers (ng/mL) (R² = 0.3215, p < 0.0001). D Correlation between platelet count (PLT) (10⁹/mL) and the ln CTC (x/7.5 mL) (p < 0.0009, R² 0.167). E Correlation between platelet count (PLT) (10⁹/mL) and the ln Dim (ng/mL) (p < 0.016)

Fig. 3

CTC count distribution cohort 2

Fig. 4

Cohort 2. A Kaplan–Meier estimates of OS (days) in patients with MBC for those with < 5 CTCs per 7.5 mL of whole blood and those in the group with ≥ 5 CTCs in 7.5 mL of whole blood (n = 92). (HR 4.167, p < 0.0001). B Relationship between the ln D-dimers (ng/mL) versus OS (days) (n = 84) (R² = 0.252, p < 0.0001). C Relationship between ln CTC (x/7.5 mL) and ln D-dimers (ng/mL) (n = 92) (R² 0.3354, p < 0.0001). D Relation between platelet count (PLT) (10⁹/mL) and the ln CTC (x/7.5 mL) (n = 92) (R² 0.1902, p = 0.004). E Relation between platelet count (PLT) (10⁹/mL) and ln D-dimers (ng/mL) (R² 0.1947, p < 0.001)

Fig. 5

Cohort 2. A Regression analysis between ln CTC and ln tdEVs. (R² 0.743, p < 0.0001) B Relation between ln tdEVs and OS (p < 0.001)