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Interim Reports Published on Two European Breast Cancer Prevention Trials
In two articles published today in the journal Lancet, European scientists reported that they found no significant difference in the number of breast cancer cases between women taking tamoxifen and women given a placebo. The failure to detect a difference between these groups is in contrast to the approximately 45 percent reduction in breast cancer incidence in women taking tamoxifen in the Breast Cancer Prevention Trial (BCPT). The BCPT results were announced in April of this year by the National Cancer Institute (NCI) and the National Surgical Adjuvant Breast and Bowel Project (NSABP), a Pittsburgh-based research network supported by NCI. The European studies that are the subject of the new articles are smaller in size than the BCPT, and there are differences in the populations studied that may account for the different conclusions.
1. What are the findings of the European studies?
Preliminary reports from the two European trials of tamoxifen did not find a statistically significant difference in the number of breast cancer cases between women taking tamoxifen and those taking a placebo.
2. What are the findings of the BCPT?
The BCPT found a highly significant reduction in breast cancer incidence in women at greater-than-average risk of breast cancer. The group of women taking tamoxifen in this study had 45 percent fewer cases of breast cancer than the group taking a placebo. The BCPT also documented certain serious side effects of tamoxifen, most notably vascular events and endometrial cancer.
3. Are there studies in addition to the BCPT that indicate that tamoxifen can prevent breast cancer?
The BCPT was based on earlier observations on the effects of tamoxifen in women who already had breast cancer. It was noted that the women who took tamoxifen had a reduced incidence of new breast cancers in the opposite breast. This observation formed the basis for the BCPT, which has confirmed that tamoxifen can prevent breast cancer in healthy women at elevated risk.
4. What features of the European studies might account for the differences with the BCPT?
The European studies were of smaller size than the BCPT. Included in the study in the United Kingdom were 2,471 women, and 5,408 participated in the Italian study. By comparison, the BCPT included 13,388 women. The BCPT included women with greater-than-average risk whereas the European studies involved women at lower risk than those in the BCPT. Another difference in the studies involved the use of estrogen hormone replacement therapy among a significant fraction of the participants in the European studies.
5. How may the number of participants influence the findings of the studies?
The number of participants in prevention trials is a major determinant of the likelihood of reliably detecting any differences that may exist between the tamoxifen and placebo groups. The larger the groups involved, the more likely it is that true differences between the groups will be detected with high probability. In contrast, the smaller the number of participants the more likely it is that any differences seen may be due to chance alone, or that real differences might be missed. In the case of the BCPT that involved 13,388 participants, the 45 percent reduction in breast cancer incidence seen with tamoxifen is highly statistically significant, and the chances of this size reduction in breast cancer being a "fluke" is less than 1 in 10,000.
6. How might the differences in risk of breast cancer affect the findings of the studies?
The biggest impact of a difference in the intrinsic risk of participants relates to the number of cases that are observed in the study. More cases occur in a study involving women at increased risk. The number of breast cancer cases in the BCPT was 329 (invasive plus non-invasive) whereas only 70 cases occurred in the UK study and only 41 in the Italian study. Of the 329 cases in the BCPT, 213 were in the placebo group and only 116 were in the tamoxifen group. This difference in case numbers between the groups is very significant. For the larger of the European studies, the numbers of cases were 36 and 34, respectively. For the smaller of the two studies, the numbers of cases were 22 in the placebo group and 19 in the tamoxifen group. The larger number of cases in the BCPT provides more confidence that the observed differences are real.
7. How might participants' use of estrogen hormone replacement therapy affect the findings of the European studies?
Tamoxifen can interact with the same receptor on cells that binds estrogen. Consequently, there is a theoretical possibility that estrogen use may block the effect of tamoxifen. In the two European studies, 14 percent or 42 percent of the participants were taking estrogen. In the BCPT, the use of estrogen was not permitted so that the effect of tamoxifen alone could be evaluated.
8. Were the BCPT results released too early?
No. An integral part of the BCPT was an independent Endpoint Review, Safety Monitoring, and Advisory Committee. At its regularly scheduled meeting in March of 1998, this committee concluded that the BCPT's primary question--whether tamoxifen can prevent breast cancer in women at greater-than-average risk--had been answered. It was concluded that the value of additional information that might be gained from continuing the study did not outweigh the benefits of making tamoxifen available to the participants in the placebo group and other women at increased risk of breast cancer. The NSABP and NCI decided to inform participants of the findings, and the trial results were made public in April.
9. How should the new publications about tamoxifen affect a woman's decision of whether or not to use tamoxifen in preventing breast cancer?
The NCI's confidence in the results of the BCPT showing that tamoxifen can reduce breast cancer in women at increased risk remains firm. A woman considering tamoxifen should discuss with her physician both the potential benefits of tamoxifen based on her personal breast cancer risk profile as well as the potential side effects of tamoxifen. The weighing of potential benefits and potential side effects is a personal decision.
10. What additional studies will be of value in assessing tamoxifen for prevention of breast cancer?
The NCI is pleased that the European studies are continuing. The very features of the trials that may account for the differences with the conclusions of the BCPT may yield new information about tamoxifen and breast cancer. For example, the European studies may provide valuable data regarding tamoxifen use by women at lower risk as well as insights into the impact of estrogen hormone replacement on tamoxifen's effects. The BCPT has provided a foundation for additional studies. NCI and the NSABP will later this year begin recruitment for a head-to-head study comparing tamoxifen with raloxifene, a related compound.
The NCI remains confident in the results of the BCPT, a study that included 13,388 women at greater-than-average risk for breast cancer. For women at increased risk of breast cancer, tamoxifen can reduce that risk. The decision of whether to use tamoxifen for prevention of breast cancer is an important and personal decision, and a woman should discuss both the benefits and the risks associated with tamoxifen use with her physician.