For two decades, tamoxifen has been the endocrine treatment of choice in women with breast cancer. Although the relationship between tamoxifen and endometrial cancer has been recognized for some time, it was believed that most of these cancers were prognostically favorable and that the benefits of reduction in recurrent breast cancer outweighed the threat of endometrial malignancy. However, the characteristics and prognosis of endometrial cancer following tamoxifen therapy have not been assessed in large trials, and its benefit as a preventive therapy against breast cancer in healthy women is unclear. Bergman and colleagues assessed the relationship between tamoxifen therapy and the risk of endometrial cancer.

The authors conducted a case-control study (an expansion of their previous study) with the primary outcomes assessing all cases of histologically verified endometrial cancer occurring at least three months after a diagnosis of breast cancer in women living in the Netherlands between 1987 and 1997. In the case group, 309 women with endometrial cancer following breast cancer were individually matched with three women in the control group (860 women with breast cancer but without endometrial cancer) by date of birth and date of diagnosis of breast cancer. For 10 of the 309 women, no controls could be matched, and data for these 10 were included only in survival analyses.

The median interval between the diagnosis of breast cancer and endometrial cancer was 40 months. At the time of diagnosis, most women were at least 55 years of age and were postmenopausal. Age at the time of breast cancer diagnosis was matched within one year for 84 percent and within two years for 95 percent of women in the control group. Of the 309 women in the case group, 108 (36.1 percent) took tamoxifen compared with 245 of the 860 women in the control group (28.5 percent).

The risk of endometrial cancer increased with duration of tamoxifen use, regardless of adjustment for duration and dosage, with relative risks of 2.0 for two to five years of use and 6.9 for at least five years of use compared with those who did not take tamoxifen. The risk did not decrease after discontinuation of tamoxifen and was not modified by other risk factors for endometrial cancer. The relative risk after five years of therapy was almost seven times greater in women who took tamoxifen. Factors such as weight, body mass index, hormone replacement therapy and other hormonal therapy increased the risk of endometrial cancer. Endometrial cancers of different types and stages were associated with tamoxifen use. Long-term use was more associated with endometrial cancer of FIGO stages III and IV and to malignant mixed mesodermal tumors or sarcomas of the endometrium. Twenty-one women in the case group died of endometrial cancer after a median follow-up of 30 months. The overall five-year survival rate was significantly worse for those who took tamoxifen compared with those who did not (40 percent versus 64 percent, respectively). The three-year endometrial–cancer-specific survival rate was worse: 76 percent in those with five or more years of tamoxifen use; 85 percent among those with two to five years of use and 94 percent among those who had not taken tamoxifen.

The authors conclude that the survival benefits of tamoxifen in the treatment of women with breast cancer far outweigh the adverse effects. They calculate that in 10 years of tamoxifen use, 20 additional endometrial cancers would develop in 1,000 women. Three to five of these cancers would be at advanced stages (FIGO stages III or IV). Their finding of a less favorable prognosis of endometrial cancer following long-term tamoxifen therapy suggests the need to question the prophylactic use of this agent in healthy women who are at increased risk of breast cancer.