For definition of Groups, see Preamble Evaluation.
VOL.: 66 (1996) (p. 253)
CAS No.:
Chem. Abstr. Name: (Z)-2-[4-(1,2-Diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine
CAS No.:
Chem. Abstr. Name: (Z)-2-[4-(1,2-Diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine,
2-hydroxy-1,2,3-propanetricarboxylate (1:1)
Tamoxifen has been available since the early 1970s for the first-line treatment of metastatic breast cancer in postmenopausal women. Since the 1980s, it has become the therapy of choice for this condition. Tamoxifen has also become the adjuvant therapy of choice for treatment of postmenopausal, node-positive women with positive oestrogen-receptor or progesterone-receptor levels and, since the early 1990s, for the treatment of postmenopausal, node-negative women with positive oestrogen-receptor or progesterone-receptor levels. It is also widely used in treating postmenopausal receptor-negative women and premenopausal women with node-negative, receptor-positive disease. When used as adjuvant therapy, tamoxifen reduces the annual rates of both death from and recurrence of breast cancer by about 25%. Tamoxifen is commonly given at doses of 20 mg daily for periods of two to five years in the adjuvant setting, although doses of up to 40 mg daily have been used in the past. Several clinical trials are in progress to study the efficacy of tamoxifen in preventing breast cancer in healthy women believed to be at high risk of developing the disease.
Tamoxifen has been widely adopted as the first-line therapy of choice for hormone-responsive male breast cancer and is frequently used as adjuvant therapy for oestrogen receptor- or progesterone receptor-positive male breast cancer.
Tamoxifen is registered for use in nearly 100 countries and cumulative use since 1973 is estimated at 7 million patient-years.
5.2 Human carcinogenicity data
The potential effect of tamoxifen in increasing the risk of endometrial cancer has been reported in one adequate cohort study, four adequate case-control studies and 14 randomized controlled trials.
In the cohort study, based on follow-up of registered cases of breast cancer in the population-based Surveillance, Epidemiology and End Results (SEER) database in the United States, the only available data on therapy were those reported at the time of initial registration. Both groups of women with reported tamoxifen use and those with no such reported use had elevated rates of endometrial cancer compared with the rates expected from the SEER database as a whole. The risk was significantly greater for women with reported tamoxifen use. The similar stage distribution in the two groups suggests a lack of serious detection bias in this study. The absence of hysterectomies could not be confirmed in this study.
The case-control studies were based on the identification of a series of women with breast cancer who had subsequently been diagnosed with endometrial cancer, with tamoxifen exposure assessed in comparison with breast cancer patients who had not developed endometrial cancer. In two of these, case and control selection was based on the records of population-based cancer registries, and two used the same source as well as hospital-based cancer registries. For the Swedish study, although an increased risk of endometrial cancer for tamoxifen use was found, the only information on treatment was that recorded in the cancer registry. Further, the absence of hysterectomy in the control series could not be confirmed. For the remaining three case-control studies, more detailed data on treatment and on hysterectomies were obtained from medical records. In the studies in France and the Netherlands, a nonsignificant elevation of risk for endometrial cancer with use of tamoxifen was found, with a significant increase in risk with increasing duration of therapy in one. In the United States study, which reported on shorter duration of use, the point estimate of risk was less than unity.
Although several potential confounders were not systematically addressed in most studies, the Working Group considered that these were unlikely to have had a major effect on the reported relative risks.
In most of the randomized trials, small numbers of endometrial cancers were reported, and for many the data were not reported in a way that corrected for the greater survival time in most trials of the tamoxifen-treated patients compared to the control series. In two of the largest trials, however, there was a strong and statistically significant association between risk for endometrial cancer and use of tamoxifen. Although there may have been a tendency for publication bias and there is some possibility of a detection bias as a result of investigations in women with side-effects from tamoxifen, the magnitude of the risk found in the two large trials is unlikely to be explained by such biases. Further, for the trials that reported deaths in women with endometrial cancer, to date there have been eight deaths in women allocated to tamoxifen treatment groups and one in those not allocated to tamoxifen.
One case series reported significantly more high-grade endometrial tumours in tamoxifen-treated cancer patients than in patients without prior tamoxifen use. However, in at least six other studies, this difference was not found.
The SEER-based cohort study found a significantly reduced risk for contralateral breast cancers in the tamoxifen-treated women, compared with women with no reported tamoxifen use. The case-control study from the United States also reported a significant reduction of risk for contralateral cancers of the breast following tamoxifen use.
Although for some small trials there seemed to be little difference in the numbers of contralateral breast cancers in tamoxifen-treated women compared with controls, for the large trials, there was a substantially and significantly reduced risk for contralateral breast cancer in tamoxifen-treated women compared with controls. Further, in an overview analysis of nearly all trials published in 1992 with data available to 1990, there was a significant reduction of 39% in contralateral breast cancers in the tamoxifen-treated groups.
For all other cancer sites, no significant excess of any cancer has been found in either the cohort study or the trials. Although an excess of gastrointestinal cancer was reported following a combined analysis of three Scandinavian trials, this has not yet been confirmed by other studies.
5.3 Animal carcinogenicity data
Tamoxifen was tested for carcinogenicity by oral administration in one study in mice and in eight studies in rats, only one of which was a formal two-year study. In mice, the incidences of benign ovarian and testicular tumours were increased. In rats, tamoxifen induced preneoplastic liver lesions and benign or malignant liver tumours. In one study, the incidence of some tumours in hormone-dependent tissues was decreased, including in the mammary gland, although reduced weight gain may have been a contributing factor. In two studies in which tamoxifen was tested by subcutaneous implantation in intact or ovariectomized female mice, it inhibited mammary tumour development in both.
In mice, tamoxifen was reported to inhibit 3-methylcholanthrene-induced cervical cancer and virus-induced leukaemia. In several studies in both male and female rats, tamoxifen enhanced the hepatocarcinogenicity of previously administered N-nitrosodiethylamine. In one study in rats, tamoxifen enhanced the development of N-nitrosodiethylamine-induced kidney tumours. In a number of studies in rats, tamoxifen inhibited 7,12-dimethylbenz[a]anthracene-induced mammary tumour development. In two studies in hamsters, tamoxifen inhibited hormonal carcinogenesis induced by 17b-oestradiol in the kidney and zeranol in the liver.
5.4 Other relevant data
Orally administered tamoxifen is well absorbed and maximum plasma levels are reached in about 5 h. Steady-state concentrations of tamoxifen in humans are reached in 3-4 weeks and those of the primary metabolite, N-desmethyltamoxifen, in about eight weeks. Tissue concentrations tend to be higher than plasma concentrations. Metabolism involves phenyl hydroxylation, alkyl hydroxylation, demethylation and N-oxide formation. Metabolism results in more products in man and rats than in mice. Much higher oral doses of tamoxifen are required for rats or mice to achieve plasma concentrations similar to human levels.
Tamoxifen is an antioestrogen with complex pharmacology encompassing variable species-, tissue-, cell-, gene-, age- and duration of administration-specific effects from oestrogen-like agonist actions to complete blockade of oestrogen action. This complexity is consistent with the various, and sometimes paradoxical, effects that have been associated with tamoxifen administration in animals and humans.
The most frequent side-effects of tamoxifen administration are hot flushes and vaginal discharge. Tamoxifen has effects on the human uterus, inducing atrophy, hyperplasia and, less frequently, polyps. Randomized placebo-controlled trials revealed a slight increase of thromboembolic events, but also a protective effect regarding myocardial diseases, according to hospital admission rates and deaths. Tamoxifen administration has been shown to decrease blood total cholesterol and low-density lipoprotein-cholesterol concentrations in a number of studies. Several preliminary trials have suggested mildly positive effects of tamoxifen in preserving bone mineral density in postmenopausal women, but much longer follow-up is required to confirm t his potentially beneficial effect.
The acute toxicity of tamoxifen in experimental animals is low. In repeated-dose studies in rats, tamoxifen induced hypertrophy, but not cell proliferation, in the endometrial epithelium; endometrial hyperplasia was, however, reported in mice. Furthermore squamous metaplasia and atrophy of the uterine epithelium was observed in chronic studies in rats. Induction of cytochromes P450 and preneoplastic lesions have been detected in the livers of rats.
Ocular toxicity, including lipidosis of the retina and cornea and increased incidence of cataract, was reported in studies in rats of chronic exposure to tamoxifen.
In the presence of human, mouse, rat and hamster microsomes, tamoxifen binds covalently to protein. Tamoxifen has oestrogenic effects on human fetal genital tracts grown in athymic mice. In rats, doses above 2 mg/kg body weight produce irregular ossification of ribs in the fetus, which is thought to be secondary to reduction of the size of the uterus of the dam. No effects on the fetus have been reported in rabbits, marmosets or cynomolgus monkeys.
There is no direct evidence that tamoxifen is active in tests for gene mutation. Evidence for the genotoxic potential of tamoxifen is supported by data obtained on DNA adduct formation in rodent liver cells in vitro and in vivo, and in rodent and human liver microsomal systems; on unscheduled DNA synthesis in rat hepatocytes in vitro; and on the induction of clastogenic events both in vitro, in genetically-engineered human cells, and in vivo in rat liver.
There is evidence from 32P-postlabelling studies that three metabolites, (a-hydroxytamoxifen, 4-hydroxytamoxifen and (Z)-1,2-diphenyl-1-(4-hydroxyphenyl)but-1-ene (metabolite E) can be further metabolized to products that react with DNA. The major DNA adduct formed in rodent liver cells has been identified as (E)-(a-(N2-deoxyguanosinyl) tamoxifen. Human hepatocytes do not form detectable DNA adducts when treated in vitro with tamoxifen; they form 300-fold lower levels of adducts than rat and mouse hepatocytes when treated with a-hydroxytamoxifen.
Preliminary studies indicate that tamoxifen does not give rise to detectable levels of DNA adducts in human liver in vivo or in human endometrium in vitro and in vivo.
Mechanistic considerations
Tamoxifen increases liver tumour incidence in rats, which may involve both DNA damage leading to increased numbers of initiated cells and oestrogen receptor-mediated clonal expansion of those initiated cells.
The available evidence suggests that tamoxifen is carcinogenic in rat liver by a genotoxic mechanism. Preliminary information from studies of human tissues suggests that humans are less susceptible to the genotoxicity of tamoxifen. Tamoxifen also possesses tumour-promoting activity in the rat liver.
Several studies have shown that the liver contains significant quantities of oestrogen receptor in hepatocytes, Kupffer cells and endothelial cells.
Tamoxifen acts as an oestrogen agonist and/or antagonist by binding directly to the oestrogen receptor. In some tissues, such as breast, tamoxifen exhibits antioestrogenic properties by binding to the oestrogen receptor with high affinity. The tamoxifen-oestrogen receptor complex is incapable of binding to DNA-responsive elements. Thus, oestrogen receptor binding does not result in normal transcriptional activity. In other tissues, such as bone and liver, tamoxifen acts as a partial agonist, possibly because cells from those tissues contain a different array of DNA binding sites, thereby leading to typical oestrogen-mediated changes in gene expression and subsequent biological effects on growth and differentiation. Therefore, tissue-specific effects of tamoxifen-oestrogen receptor on gene expression may be involved in the ability of tamoxifen to increase or decrease tumour risk.
5.5 Evaluation
There is sufficient evidence in humans for the carcinogenicity of tamoxifen in increasing the risk for endometrial cancer and there is conclusive evidence that tamoxifen reduces the risk for contralateral breast cancer in women with a previous diagnosis of breast cancer.
There is inadequate evidence in humans for the carcinogenicity of tamoxifen in other organs.
There is sufficient evidence in experimental animals for the carcinogenicity of tamoxifen.
Overall evaluation
Tamoxifen is carcinogenic to humans (Group 1) and there is conclusive evidence that tamoxifen reduces the risk of contralateral breast cancer.
(Dr Cuzick dissociated himself from the evaluation process because he considered that the range of evaluation statements available within the framework of the Monographs was not suitable for this agent.)
For definition of the italicized terms, see Preamble Evaluation
Synonyms for Tamoxifen
See Also:
Toxicological Abbreviations