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Factor V Leiden mutation, thromboembolism risk, and tamoxifen

June 28, 2010

Study Design: A case-control study in 34 Cancer and Leukemia Group B (CALGB) institutions
Study Eligibility: Cases were women who developed a venous or arterial embolism or deep venous thrombosis while taking adjuvant tamoxifen for stages I, II, or IIIa breast cancer. Controls were women who did not develop a venous or arterial embolism while taking adjuvant tamoxifen for Stages I, II, IIIa breast cancer at a CALGB institution, though not necessarily on a CALGB treatment trial.
Enrollment: 124 cases and 248 controls
Research Question: Is Factor V Leiden mutation associated with elevated thromboembolism risk in early breast cancer patients who took tamoxifen?

Tamoxifen is a common breast cancer drug that has been shown to improve disease-free and overall survival for pre- and postmenopausal women with hormone receptor-positive breast cancer. But tamoxifen has been associated with thromboembolic events. Thromboembolism occurs when a blood clot forms and is carried through a blood vessel, eventually becoming lodged and causing a blockage. Factor V Leiden (FVL) mutation has also been found to increase the risk of thrombosis in patients with other risk factors that include the use of hormone replacement therapy (HRT), or high-dose oral contraceptives, and pregnancy. FVL mutation results in resistance to anticoagulant activity of another activated protein called protein C. In this case-control study, the investigators have hypothesized that an association might exist between having a FVL mutation and tamoxifen-associated thromboembolism.

The study population consisted of 412 breast cancer patients who had received tamoxifen as adjuvant therapy for early breast cancer. Enrolled between January 15, 1999 and April 1, 2005, the patients were accrued by physicians affiliated with CALGB. However, the patients were not required to be on a CALGB treatment trial. Cases and controls were interviewed regarding pregnancy history, menopausal status, HRT history, smoking status during adjuvant tamoxifen therapy, and thromboembolism history. To determine FVL mutation status, blood specimens were obtained and analyzed.

Among cases and controls, past hormone use, blood clot history, and breast cancer stage differed with more women being diagnosed at stage I among the cases. The controls had received postmenopausal HRT for a significantly longer period of time before breast cancer diagnosis than the cases. More cases also smoked during adjuvant tamoxifen therapy compared to the controls. The investigators also found that significantly more cases had FVL mutations compared to the controls and that the likelihood of having thromboembolism was significantly increased among women with FVL mutation who had adjuvant tamoxifen.

Although the study found that FVL mutation was associated with elevated thromboembolism risk among women receiving adjuvant tamoxifen for early breast cancer, there were several limitations in the study. Among women with thromboembolism, family history of thromboembolism was more prevalent but not limited to women with FVL mutation. Family history of thromboembolism was not confirmed with medical records and the participants were not evaluated for other underlying hereditary diseases such as deficient protein C, protein S, or anti-thrombin III. Also, data such as body mass index, recent surgery, or other immobilization which have been shown to decrease the risk of thromboembolism were not collected. In addition, among women who took tamoxifen in two major breast cancer prevention trials (i.e., IBIS-I and NSABP P1) FVL carriers did not have elevated risk of thromboembolism. As research findings have been contradictory, continued follow-up and more studies on the relationship between FVL mutation and tamoxifen are needed.