The use of tamoxifen to prevent breast cancer is controversial. Many ethical issues and other concerns about exposing healthy women to an increased risk of endometrial cancer and vascular events have been overshadowed by the impressive reductions in breast cancer reported by an American trial, the National Surgical Adjuvant Breast and Bowel Project (NSABP-P1). In that four-year clinical trial, tamoxifen appeared to prevent approximately one half of invasive and non-invasive cancers in women at increased risk of breast cancer. Powles and associates report the results of an interim analysis of a British study of tamoxifen for the prevention of breast cancer.
The study included women 30 to 70 years of age with an increased risk of breast cancer because of a family history. They were randomized to receive either 20 mg of tamoxifen daily or placebo. The preliminary results reported in this study are based on 2,471 women. Median follow-up was 70 months. A total of 156 patients completed the eight years of therapy; 877 patients stopped therapy because of side effects (320 women receiving tamoxifen and 176 women receiving placebo) or for other reasons.
The frequency of breast cancer was found to be the same in the tamoxifen and placebo groups. In the tamoxifen group, breast cancer developed in 34 women compared with 36 women in the placebo group. Nulliparous women were found to have a twofold increase in the risk of breast cancer compared with women with children. Women who were receiving hormone replacement therapy at the time of entry into the study had an increased risk of breast cancer, but those who started hormone replacement therapy during the study had a decreased risk. However, after adjusting for confounding variables, there appeared to be no interaction between the use of hormone replacement therapy and any effect of tamoxifen in preventing breast cancer.
Four cases of endometrial cancer occurred in the tamoxifen group, compared with one case in the placebo group. Nine deaths occurred in the group treated with tamoxifen (four of which were from breast cancer), compared with six deaths in the placebo group (one of which was from breast cancer). Deep venous thrombosis occurred in four patients receiving tamoxifen and in two patients receiving placebo. Three patients receiving tamoxifen had pulmonary embolism compared with two patients receiving placebo.
The authors state that they were surprised to find no overall reduction in the occurrence of breast cancer in patients receiving tamoxifen. They note that one reason for the difference in the findings from the NSABP trial and their study may relate to study populations. Entry criteria for the British study were based mainly on a strong family history, with an associated risk of inheriting a gene that predisposes the women to breast cancer. Entry criteria for the NSABP study were primarily based on nongenetic risk factors. Another reason for the discordant findings may relate to the duration of follow-up. The median follow-up for the British study was nearly six years, compared with three to five years in the NSABP trial.
The authors conclude that there remains doubt about what the findings in the NSABP trial mean in terms of breast cancer prevention. Further study is necessary to characterize the subgroups in which the benefits of tamoxifen outweigh the risks and to justify the use of tamoxifen for the prevention of breast cancer.