Tamoxifen therapy and carcinogenic risk.

It is quite remarkable that tamoxifen, a drug that is so effective in the treatment of breast cancer, should have so low a toxicity profile. Since 1971, tamoxifen has been used to treat many millions of patients for periods sometimes in excess of 10 years, in doses sometimes eightfold higher than the usual dose; yet the incidence of serious toxic effects from tamoxifen has been almost negligible. This perhaps fortuitous result, however, should not induce a sense of complacency, since tamoxifen's use is now widespread and includes large numbers of patients with a high cure rate and very long life expectancy, as well as healthy women in chemoprevention trials. Within these settings, considerable caution is warranted in the design and evaluation of clinical trials and treatment schedules of tamoxifen. Perhaps the deepest concern is the carcinogenic potential of tamoxifen, since it is a proven carcinogen in the rat (7,2). Tamoxifen itself is not genotoxic but is activated by cytochrome P450 drug-metabolizing enzymes to form reactive intermediates that bind covalently to DNA to create adducts (3) and carcinogenic risk (4-7). Local detoxifying mechanisms and DNA repair will limit the likely expression of clinical cancer, and the balance of all these factors will determine the risk in any organ, in any species. For example, in several strains of rat, tamoxifen can cause cancers in the liver, but not in other tissues, at blood levels similar to those in women being treated for breast cancer with this agent (2,8). At these doses, the carcinogenic potential in the liver varies according to the strain of rat (9); carcinogenicity has not been reported in other species. Therefore, quantitative prediction from these experimental data of any human risk, in any tissue, is not possible. At this time, all we can say is that tamoxifen is potentially carcinogenic in any human tissue that has the capability to generate the reactive metabolites and that possesses the cellular characteristics needed for expression of the carcinogenic potential. The prediction of carcinogenic risk is complicated further by the observed estrogenic effects of tamoxifen on various tissues, including the endometrium, a tissue in which estrogen will promote clinical cancer (10). The possible synergism of genotoxicity with estrogenic promotion by tamoxifen makes the uterus a prime site for potential carcinogenic risk in humans. Hormone promotion may also be important in other tissues, such as the ovary. Other organs potentially at special risk in humans are those with a high cellular proliferation rate, such as bone marrow, and those tissues that may be exposed to high levels of the carcinogenic metabolites, such as the liver, stomach, and colon. Surprisingly, the clinical data are unclear about carcinogenic risk, in spite of extensive tamoxifen use. This situation may exist, in part, because its early use was predominantly in women with poor-prognosis, relapsed disease. Since then, tamoxifen has been used in adjuvant trials; unfortunately, however, many of these trials have had inadequate surveillance for second tumors. This omission occurred because of the lack of awareness of carcinogenic risk; therefore, new primary cancers may not have been carefully distinguished from metastatic relapse or may not have been recorded as separate events. More accurate assessment is now under way; but, in the meantime, it is necessary to rely on retrospective assessment within individual clinical trials, data from case-control studies, and the evaluation of any surrogate events, all of which have serious limitations for accurate assessment of risk. As yet, there are few intermediate markers of carcinogenic risk, although it is reassuring to note that, within a small clinical trial, there was no evidence of any increase in DNA adducts in the livers of women being treated with tamoxifen compared with those of control subjects (77). More extensive evaluation of other tissues from women taking tamoxifen is needed. Retrospective review of clinical trials of tamoxifen has shown no increased risk of acute leukemia or other hematopoietic cancers (12-14). These malignancies are diagnostically well defined and occur early relative to solid cancers. The incidence of other malignancies has not been so clearly defined in these retrospective studies. The Swedish study (12), using a tamoxifen dose of 40 mg per day for 2-5 years with a median follow-up of 9 years, and two other Scandinavian trials, using a tamoxifen dose of 30 mg per day for 1 year (72), all indicated a dose-dependent, increased risk of endometrial cancer in postmenopausal women; this finding is in keeping with the reported increased incidence of endometrial cancer in the patients receiving tamoxifen in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial (13). The estimated relative risk of twofold to