European Tamoxifen Prevention Studies Do Not Agree With American Results
Sources: Veronesi U, et al. Lancet 1998;352:93-97; Powles T, et al. Lancet 1998;352:98-101.
Motivated by the american breast cancer prevention Trial that indicated a 45% reduction in breast cancer incidence with prophylactic tamoxifen treatment, Veronesi and colleagues from the Italian Tamoxifen Prevention Study presented a preliminary analysis of their clinical trial that began in 1992. A total of 5408 women was randomized to tamoxifen 20 mg daily, and the trial was scheduled to complete five years of treatment. There was no difference in the frequency of breast cancer between the tamoxifen and placebo arms. In women using postmenopausal hormone therapy, there were eight cases of breast cancer in the placebo group and only one in the tamoxifen arm; although this was a statistically significant difference, it is a low power conclusion, based on such a small number of cases.
Powles and colleagues began their clinical trial in 1993 and presented their analysis of 2471 women. The frequency of breast cancer was the same in the tamoxifen and placebo arms. In this trial, there was no effect of postmenopausal hormone therapy on breast cancer occurrence with tamoxifen treatment. Although the number of women in this trial was smaller than the others, the duration of follow-up was longer, with many women achieving six and eight years of follow-up.
Both studies raise doubt regarding the American report and deplore the early termination of the American study.
Comment by Leon Speroff, MD
An excellent editorial accompanies these articles, written by Kathleen I. Pritchard, an epidemiologist from the University of Toronto in Canada.1 A consideration of power calculations indicates that the smaller size of these studies did not make it impossible to demonstrate an effect comparable to the American trial. A possible explanation is that both the Italian and U.K. trials contained a larger nuber of younger women. Because the effect of tamoxifen in the American trial was confined to estrogen receptor positive cancers in older women, this difference in age could contribute to a lower effect. Another possibility, and one that is worrisome, is that longer durations of treatment, as in the European trials, could allow the emergence of more aggressive tamoxifen-resistant tumors, as has been observed with adjuvant tamoxifen treatment that lasts no longer than five years. Another contributing factor is a dissimilarity in risk factors, especially a difference in family history in the Italian study.
These results lend credibility to the argument that estrogen and tamoxifen are exerting promotional and anti-promotional effects on pre-existing tumors, not causing and preventing breast cancer. To answer this, the clinical trials must continue, with long follow-up, especially to document breast cancer mortality in these groups of women. For this reason, the Italian and U.K. investigators both decided to continue their trials. In addition, there is a fourth tamoxifen prevention trial, the International Breast Cancer Intervention Study (which currently has enrolled about 4000 of a target of 7000 women). In view of the disagreement among the American, Italian, and U.K. trials, the International Study has decided to keep its study blinded and to continue as planned.
These results strongly support the clinician, who advises women seeking tamoxifen preventive treatment that the final answers are not in, and that the final accounting from the European and International trials will be necessary before informed decision-making is possible.
Reference
1. Pritchard KI. Lancet 1998;352:80-81.
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