Tamoxifen (Nolvadex) has been the endocrine treatment of choice for all stages of breast cancer for nearly a decade. Millions of women have received and are currently receiving tamoxifen(Drug information on tamoxifen) worldwide, while large-scale randomized trials have been launched to investigate the drug's merit as a chemopreventive agent.
Tamoxifen's primary pharmacologic action is to block the growth-promoting effects of estrogens(Drug information on estrogens) on breast cancer. In addition, tamoxifen exerts an array of both antiestrogenic and estrogenic activities in different tissues throughout the body. It is the estrogenic properties that account for the reduction of total cholesterol and the preservation of bone mineral density reported in tamoxifen-treated women--two very welcome "side-effects" of tamoxifen treatmentthat could have a major impact in the long-term clinical outcome for breast cancer patients and participants in the chemoprevention trials. In contrast, the estrogenic properties have been associated with its most publicized potential side effectan increased risk of endometrial cancer.
In this article, we will review the beneficial effects on bone and lipids and on the reduction of contralateral breast cancer, as well as the data on endometrial cancer to try to answer the following question: do the benefits outweigh the risks?
It is well documented that women can lose up to 35% of cortical and up to 50% of trabecular bone mass over their lifetime. The role of estrogens in hindering this process has been clearly demonstrated. For this reason, there were concerns that tamoxifen, as an antiestrogen, might induce bone loss and hasten osteoporosis. Fortunately, this has been shown not to be the case. A recent review of clinical trials investigating the effects of tamoxifen on bone mineral density showed that tamoxifen has estrogenic activity, reducing bone resorption and maintaining overall bone mineral density. Interestingly, this effect was noted on both trabecular and cortical bone, with the effect on trabecular bone being more prominent. The clinical implications of such an effect include a significant deceleration in the osteoporotic process and a reduction in the incidence of hip fractures. Moreover, based on the findings that show a correlation between the duration of estrogenic treatment in postmenopausal women and the reduction of hip fractures, the implication for tamoxifen is that perhaps a similar effect would be achieved with long-term therapy.
Even for breast cancer patients, coronary heart disease (CHD) is a major cause of morbidity and mortality that increases after menopause. Thus it is important to consider the effect of tamoxifen on the lipid profile and how changes translate clinically. A number of investigators have reported on the effect of tamoxifen in reducing serum cholesterol levels. In fact, clinical trials have reported an average decrease of 13% in total cholesterol and a decrease of 19% in LDL cholesterol (Table 1). No clear correlation of tamoxifen treatment with changes in HDL cholesterol levels is evident from available data. Although HDL is a more sensitive indicator of risk for atherosclerosis than is LDL, there is evidence that both LDL and total cholesterol values can have profound effects on the incidence of cardiac disease. The Framingham Heart Study found that a 1% drop in total cholesterol was associated with a 2% decrease in CHD. Major clinical trials have provided supporting evidence on the implications of tamoxifen treatment related to CHD. The Scottish trial has reported that breast cancer patients treated with tamoxifen for five years have half the risk of suffering a fatal myocardial infarction compared with control patients treated with tamoxifen only on relapse. In addition, the Stockholm trial has documented a significant reduction in hospital visits for any heart disease-related problems in tamoxifen-treated patients compared with control patients not treated with tamoxifen.
Although tamoxifen may have positive side effects on bone and lipids that would result in additional lives saved, the primary benefit of tamoxifen therapy (next to the cytostatic effect on the breast tumor itself) is still the reduction in the incidence of contralateral breast cancer. The Early Breast Cancer Trialists' Collaborative Group performed an overview analysis of 133 randomized trials involving close to 75,000 women, 30,000 of whom had received adjuvant tamoxifen therapy. While appreciating the limitations of such an indirect comparison, the analysis concludes that the incidence of contralateral breast cancer in women on tamoxifen was reduced by 36% over an average follow-up period of 5.6 years. Since contralateral breast cancer constitutes the most common secondary malignancy in this group of patients, it is reasonable to expect that by reducing contralateral breast cancer, tamoxifen therapy results in lives saved.
The most worrisome adverse effect of tamoxifen treatment has been a reported increase in the detection of endometrial cancer, although there is considerable variance in the reports. Since Killackey's first report in 1985, a number of reports have appeared in the literature associating tamoxifen with endometrial cancer. We have recently reviewed the world literature and found a total of 349 cases of endometrial carcinoma reported in association with tamoxifen therapy through the end of 1995 (Table 2). Other malignant uterine histologies such as mixed müllerian tumors (MMT) and sarcomas have been reported and are listed separately. Although precise data are not available for all of these reported cases, we do know that the vast majority of patients were postmenopausal.
The daily dose of tamoxifen does not seem to play a key role; endometrial cancers were found in association with varied dosing schedules for tamoxifen. The duration of tamoxifen therapy also does not seem to be important in this respect. In contrast to what some investigators have argued, we do not see a massive increase in the frequency of endometrial cancer reported with tamoxifen duration longer than two years.
One point of interest is the aggressiveness of the reported endometrial tumors with regard to grade and stage. Some recent reports suggest that tamoxifen is associated with highly aggressive endometrial cancer.[9,10] To address this issue, we analyzed the grade and stage of the endometrial carcinoma cases reported in the literature. As depicted in Figure 1, the great majority of these tumors are locally confined (stage I) and of low grade (grade 1 or 2). For comparison, we have included the grade and stage of endometrial cancer cases in the general population as reflected in the Surveillance, Epidemiology and End Results (SEER) data derived from a total of 12,717 patients. Clearly, endometrial cancer in tamoxifen-treated women is similar in grade and stage to cases reported in the general population and is a disease with a relatively favorable outcome.
As far as the incidence of endometrial cancer is concerned, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 study has reported that for women on tamoxifen there is only a two- to threefold increase in the relative risk for endometrial cancer, which equals two to three per 1,000 women annually.
Tamoxifen, as any other drug, particularly anticancer drugs, has side effects. Compared with chemotherapeutic regimens commonly used for the treatment of advanced breast cancer, tamoxifen appears to be much safer and to be considerably better tolerated by the patient. Clearly, the issue related to tamoxifen use becomes one of weighing the benefits vs the risks. On the positive side, tamoxifen has beneficial effects on bone and lipids which, in conjunction with the reduction in contralateral breast cancer, will translate into lives saved. On the negative side, tamoxifen has an association with an increase in the detection of endometrial cancer.
If we add the most clinically significant benefits of tamoxifenthat is, its ability to prolong disease-free survival and to reduce breast cancer mortalitythen it becomes clear that the benefits of tamoxifen therapy far outweigh the risks. Tamoxifen is listed by the World Health Organization as an essential drug for the treatment of breast cancer. Indeed, an agency of the World Health Organization recently reviewed all the information concerning the links between tamoxifen and carcinogenesis and concluded that the known benefits of tamoxifen far outweigh any risks from side effects. No woman with breast cancer should be denied tamoxifen out of concern for potential gynecologic complications.