Effects of adjuvant chemotherapy on the protein C anticoagulant pathway in patients with early stage breast cancer

8563 Background: Although chemotherapy treatment is associated with an increased risk of thrombosis, the pathogenic mechanisms are poorly understood. We have previously shown that treatment of endothelial cells with adriamycin and epirubicin impairs the protein C anticoagulant pathway by downregulating EPCR (endothelial protein C receptor), an endothelial receptor required for the conversion of protein C to the anticoagulant enzyme activated protein C (APC). In this study, we examined the effects of adriamycin- and epirubicin-containing chemotherapy on the protein C anticoagulant pathway in early stage breast cancer patients. Methods: We collected blood samples from 20 patients patients with early stage breast cancer undergoing adjuvant CEF (cyclophosphamide, epirubicin and 5-fluorouracil) or CMF (cyclophosphamide, methotrexate and 5-fluorouracil) chemotherapy on days 1, 2 and 8 for the first 2 cycles of treatment. Markers of protein C generation (protein C, thrombin-antithrombin (TAT) complexes, and APC) were measured on these days. Results: Plasma protein C levels were significantly lower at cycle 2 day 8 (0.88 ± 0.14 U/ml) compared to pre-chemotherapy levels (1.07 ± 0.23 U/ml) (p=0.0036). Plasma TAT levels were significantly higher at cycle 2 day 8 (2.87 ± 0.79 μg/L) compared to pre-chemotherapy levels (2.01 ± 1.24 μg/L) (p=0.02). Based on the APC levels, the patients appear to fall into two categories in terms of their ability to generate APC. The first group (n=16) has elevated APC levels that parallel the elevated TAT levels, whereas the second group (n=4) has low APC levels despite elevated TAT levels. Conclusions: Impaired ability to generate APC in a subpopulation of patients may reflect chemotherapy-induced impairment of the protein C pathway through the downregulation of EPCR. This pilot study provides new mechanistic insights into the prothrombotic effects of chemotherapy agents. No significant financial relationships to disclose.