Breast Cancer Patients Undergoing Adjuvant Chemotherapy Do Not Acquire Activated Protein C Resistance (APC-R).

Malignancy has been known to be associated with a hypercoagulable state since Trosseau first described it a hundred years ago. This is a multifactorial process that includes (1) direct activation of the coagulation system by production of procoagulants, (2) indirect activation through release of cytokines, (3) the complex interaction between tumor cells, blood cells, and endothelium, and (4) problems associated with malignancy including surgery, immobility, and intravenous catheters. One of the most recent postulated mechanisms is acquired resistance to APC. APC is a serum protein that normally inhibits the coagulation cascade. APC-R increases the risk of venous thrombosis and can be either hereditary or acquired. The hereditary form is caused by the well-known mutation, factor V Leiden. More recently, acquired forms of APC-R have been described, and the list of possible etiologies is growing. In cancer patients, APC-R has been detected in the absence of factor V Leiden mutation, suggesting a possible cause-effect relationship between malignancy and acquired APC-R. A possible mechanism is thought to be an increase in serum levels of another coagulation protein, factor VIII. However, the exact incidence, mechanism, and possible role of exposure to chemotherapeutic agents remain unclear. This pilot study was designed to study whether chemotherapy can induce APC-R in early stage breast cancer patients who were rendered cancer-free surgically, and then received adjuvant chemotherapy.

We enrolled women with stage I - III breast cancer between July 2007 and December 2008. Personal histories were obtained for all patients to document the absence of any prior history of venous thrombosis. Patients with a known history of any hypercoagulable state such as factor V Leiden and prothrombin G20210A mutations were excluded. Also, patients were excluded if they had any other cancers or taking anticoagulants. Typical chemotherapies included cyclophosphamide, doxorubicin, docetaxel and paclitaxel. Venous blood samples were drawn in citrated vacuum tubes on the first and last day of chemotherapy and centrifuged within 4 hours. These samples were coded and stored at – 70° C. The APC-R was measured in thawed plasma by a functional clotting test system (Dade Behring assay, Behring Diagnostics Inc, Cupertino, CA).

A total of 31 women were enrolled in the study. These patients were treated with either lumpectomy or mastectomy and opted to undergo adjuvant chemotherapy. The study was approved by the health system Institutional Review Board. Most study subjects, 28 (90%), were in the 42-68 age group. Only 2 women (6%) were ages 30-39, and 1 woman (3%) was age 20-29. Seventeen (54.8%) of our study participants were menopausal. Twenty (56%) of the study subjects had undergone lumpectomy, and 11 (38%) had a total mastectomy. The average postoperative duration before receiving chemotherapy was 47.3 (SD 26.5) days. None of the 31 samples tested before chemotherapy had APC-R. When the test was repeated on the last day of chemotherapy, none of the samples showed evidence of acquired APC-R (p = 1). The patients were monitored clinically during their routine chemotherapy visits and no evidence of either arterial or venous thrombosis was noted.

Although acquired APC-R after chemotherapy has been increasingly reported in the literature in the last few years, our study clearly indicates that in early stage breast cancer patients who were rendered cancer-free surgically, there was no development of APC-R after chemotherapy. Our study has several limitations. First, the sample size was small. Even with a larger sample size, it is very unlikely that acquired APC-R would be detected, as not a single sample out of 31 converted to APC-R after chemotherapy. Secondly, the duration of follow up was limited; patients were not tested or monitored clinically for several months after receiving chemotherapy and this could have affected our results. Thirdly, the study subjects were mainly caucasian women and the results cannot be extrapolated to men or other ethnicities. Our study indicates that there is no relationship between undergoing adjuvant chemotherapy and subsequently acquiring resistance to APC in patients with early stage breast cancer. Further studies should look at the possible connection between chemotherapy and acquired APC-R in other malignancies.

No relevant conflicts of interest to declare.