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© 2002 American Society for Clinical Oncology
Retrospective Assessment of Hypercoagulability in Breast Cancer Prevention Trial
Baptist Cancer Institute, Jacksonville, FL To the Editor:The Breast Cancer Prevention Trial (BCPT) conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) demonstrated that the use of tamoxifen in women at high risk for breast cancer significantly decreased the incidence of the malignancy.1 One of the complications noted was a relative increase in venous thromboembolic disease and strokes in the group on tamoxifen as compared with placebo. This report summarizes the results of an assessment for the detection of hypercoagulability abnormalities performed retrospectively on some affected subjects who were enrolled in BCPT. At the outset of this project, there were 155 individuals recorded in BCPT who had developed phlebitis, pulmonary embolism, and strokes. The objective of this analysis was to obtain laboratory evaluations on these women to determine whether inherited and/or acquired hypercoagulability factors further predisposed them while on tamoxifen as compared with placebo. The study was retrospective and performed in blinded fashion regarding the use of tamoxifen or placebo. The principle investigators who were responsible for women reported with vascular complications were contacted, provided study numbers, and offered an opportunity for their subject(s) to participate. No subject was still on anticoagulant therapy. Samples were sent to The Blood Center of Southeastern Wisconsin where hypercoagulability testing was performed. Test results were returned to the principle investigators for transmission of clinical information to subjects. All participants signed an informed consent approved by local institutional review boards (IRB). In addition, global assurance was given by the IRB of Baptist Medical Center, Jacksonville, FL. When all the testing was completed, the subject numbers were uncoded for analysis of possible relationship to tamoxifen and placebo. There were no costs to any of the subjects or physicians; AstraZeneca (Wilmington, DE) agreed to reimburse expenses for all blood testing and shipments. After more than 1 year of attempting to get blood samples, only 24 (15%) of the 155 subjects were located and agreed to be investigated. Of these 24 subjects, 20 (83%) had abnormalities of hypercoagulability (Table 1). In this group, 50% had one defect, 30% had two concomitant abnormalities, and 20% had three or more. As reported by NSABP,1 the relative rate for deep venous thrombosis, pulmonary emboli, and stroke with the use of tamoxifen over placebo in BCPT was 1.8. In our subset, a similar ratio for use of tamoxifen over placebo was found (2.0), as shown in Table 2. The rate of discovery of hypercoagulability factors in those receiving tamoxifen as compared with placebo was 1.86, suggesting an even distribution of events with treatment groups being studied.
The high frequency of underlying hypercoagulability defects is curious and raises the suggestion that an investigation for these factors might be considered before the use of tamoxifen for breast cancer prevention. Table 2 lists the defects that were discovered as well as the identification of unblinded study medication. The appearance of six of 24 subjects with antithrombin deficiency is striking given the low frequency of this disorder in the general population. The incidence of factor V-Leiden2,3 and methylene tetrahydrofolate reductase (MTHFR) heterozygosity are more in line with anticipated frequency in the general population. MTHFR heterozygosity has been considered to have marginal pathophysiologic significance.4 When all defects are combined, there were no statistically significant findings to support a role of drug treatment in the outcome of vascular disease. Similarly, there are no statistically significant events when defects were examined individually. In fact, the high incidence of antithrombin deficiency seems to be equally spread between tamoxifen and placebo given preselection factors of the subset analysis (tamoxifen to placebo ratio of 2.0). Elevated factor VIII levels were present in eight subjects on tamoxifen as contrasted to one on placebo. Yet, some factors were skewed in the opposite direction; eg, all three cases of factor V-Leiden were in the placebo group. Unfortunately, the limited number of subjects studied represented too small a subset of the overall BCPT group, thereby limiting statistical analysis of an effect by tamoxifen. NSABP is currently analyzing data from stored cells to determine any relationship to vascular disease. However, these samples (DNA) can only assess a limited number of abnormalities (factor V-Leiden, prothrombin 20210A, and MTHFR) rather than the greater number of hypercoagulability factors in our report. As an important side note, the most common cause that impeded the ability to retrieve blood samples from affected subjects was related to the reluctance expressed by investigators. Frequently, their comments related to difficulties with presenting another informed consent to their subjects and to their IRBs, as well. They also expressed concerns anticipated with IRB approval, costs involved with added time spent by staff, and fees imposed by some IRBs. Only an occasional subject objected to the testing. Certainly, financial costs to subjects were not a factor because all expenses were covered. Had more subjects been assessed, we might have had an opportunity to address the interaction of tamoxifen to hypercoagulability with some statistical assurance. More data might have permitted correlations to menopausal status, age of subjects, length of time of drug use, and pre-existing hormone replacement therapy as well as to some of the individual defects that were discovered. REFERENCES
1. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90: 1371-1388, 1998
2. Ridker PM, Glynn RJ, Miletich JP, et al: Age-specific incidence rates of venous thromboembolism among heterozygous carriers of factor V Leiden mutation. Ann Intern Med 126: 528-531, 1997
3. Price DT, Ridker PM: Factor V: Leiden mutation and the risks for thromboembolic disease: a clinical perspective. Ann Intern Med 127: 895-903, 1997 4. Tosetto A, Missiaglia E, Frezzato M, et al: The VITA project: C677T mutation in the methylene-tetrahydrofolate reductase gene and risk of venous thromboembolism. Br J Haematol 97: 804-806, 1997[CrossRef][Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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