Page 249 - Haematologica - Vol. 105 n. 6 - June 2020

Hypercoagulation and relapse in breast cancer
relapses occurred in Luminal B HER2-neg (n=33) and in TN (n=19), while the remaining were in Luminal A (n=10), in Luminal B HER2-pos (n=3), and in HER2-pos (n=3) patients; for one patient, this information was not avail- able. The risk of recurrence was increased 4-fold (P<0.01) in patients with Luminal B HER2-neg and TN subtypes (HR=4.2, 95%CI: 2.3-7.8) compared to the remaining patients, with a DR cumulative incidence at four years of 17.6% (95%CI: 12.9-22.4) and 4.9% (95%CI: 2.4-7.5), respectively. Finally, the group of patients with DR was characterized by a higher proportion of subjects with tumor size ≥ 5 cm (P=0.011), infiltrated axillary lymph nodes (P=0.020), mastectomy (P=0.047), and Luminal B HER2-neg and TN molecular subtypes.
Hypercoagulation biomarkers and hematologic parameters
Patients had significantly higher plasma levels (P<0.01) of D-dimer, fibrinogen, and F1+2, compared to internal ref- erence values obtained from a control group of healthy subjects (Figure 2). To exclude any influence of surgery [median time to blood sampling: 43 days (5th-95th range: 26- 72 days)] on coagulation, the levels of each hemostatic marker were correlated with the time from surgery. The results showed no statistically significant correlation between time from surgery and each of the biomarkers (data not shown), even after sex and gender correction.
At enrollment, 12 patients were on thromboprophylaxis with anti-platelet agents (i.e. aspirin) and four with antico- agulants. To exclude any influence of thromboprophylaxis on thrombotic biomarker levels, we compared patients on aspirin (n=12) with those who were not (n=689), and no significant differences were found. The comparison of bio- markers between the anticoagulated (n=4) versus non-anti- coagulated (n= 697) subjects could not provide statistically reliable results due to the very small number of subjects on anticoagulants.
Hemochromocytometric tests showed most patients had low red blood cell count and hemoglobin levels as compared to the control reference range (Table 2).
Association of hypercoagulation biomarkers with tumor characteristics
Multivariate analyses were performed to search for any significant association between hypercoagulation bio- marker levels, hematologic parameters and tumor charac- teristics. According to tumor-node-metastasis classifica- tion, tumor size was a significant determinant of D-dimer (β=0.134, P=0.001) and fibrinogen (β=0.110, P=0.006) lev- els, while lymph node involvement positivity was a signif- icant predictor of D-dimer (β=0.216, P<0.001) and F1+2 (β=0.112, P=0.004) plasma levels. No significant associa- tions were found between hypercoagulation biomarkers and tumor histological subtype or grading. Similarly, no significant associations were found between hematologic parameters and tumor characteristics.
Association between hypercoagulation biomarker abnormalities and disease recurrence
Plasma levels of hypercoagulation biomarkers and hema- tologic parameters according to DR occurrence are shown in Table 3. There was no statistical difference in levels of the D-dimer, FVIIa-AT and fibrinogen between patients who experienced a relapse as compared to patients who remained disease-free during follow up, while F1+2 levels were significantly higher in the group of relapsed patients (P<0.05). Interestingly, correlation analyses showed that pre-chemotherapy levels of fibrinogen were significantly and inversely associated with time to relapse (β = -0.317; P=0.012).
A receiver operating characteristic (ROC) curve analysis was performed to evaluate the contribution of F1+2 levels to predict DR at four years of follow up. The area under the curve was 0.595. Cut-off value was set at 202.5
Figure 1. Cumulative incidence of disease recurrence in patients with resected breast cancer during four years follow up.
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