PURPOSE: To review the preclinical and clinical data on the carcinogenic potential of tamoxifen. DESIGN: A MEDLINE search on the carcinogenicity of tamoxifen was conducted and the literature reviewed. RESULTS: Because tamoxifen has estrogen-like effects on some tissues, such as the human uterus, there has been concern that tamoxifen could promote endometrial cancers in women on chronic tamoxifen therapy. Observations in some randomized trials of adjuvant tamoxifen therapy are consistent with a small, but real, increased risk of endometrial cancer in women who take tamoxifen. Since increased endometrial cancer incidence has not been observed in all studies of chronic tamoxifen therapy, there may be an element of detection bias. Laboratory studies have demonstrated that tamoxifen is hepatocarcinogenic in laboratory rats, but not in other species. This carcinogenicity in rats has been linked to the formation of DNA adducts. CONCLUSION: The incidence of endometrial cancer is increased in women who take tamoxifen. The data suggest that tamoxifen might be a tumor promoter in human endometrium. However, on the basis of the number of tumors seen by endometrial sampling of tamoxifen-treated women, the impact of tamoxifen as a tumor promoter is small. Women on chronic tamoxifen therapy should have routine annual gynecologic examinations and receive endometrial sampling only in the event of uterine bleeding. Unlike the data in rats, there is no conclusive evidence to link tamoxifen with an increased rate of hepatocellular cancer in humans; the contrasting carcinogenic potential may be attributed to substantial interspecies differences in the metabolism of tamoxifen.
