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 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 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
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.
1. Lobo RA, Pickar JH, Wild RA, et al: Metabolic impact of adding medroxyprogesterone
acetate to conjugated estrogen therapy in postmenopausal women. Obstet
Gynecol 84:987-995, 1994.
2. Bilimoria MM, Assikis VJ, Jordan VC: Should adjuvant tamoxifen therapy
be stopped at 5 years? Cancer J Sci Am 2:140-150, 1996.
3. Weiss NS, Ure CL, Ballard JH, et al: Decreased risk of fractures
of the hip and lower forearm with postmenopausal use of estrogen. N Engl
J Med 303:1195-1198, 1980.
4. Castelli WP: Cholesterol and lipids in the risk of coronary artery
disease: The Framingham Heart Study. Can J Cardiol 4:5A-10A, 1988.
5. McDonald CC, Stewart HJ: Fatal myocardial infarction in the Scottish
adjuvant tamoxifen trial. Br J Med 303:435-437, 1991.
6. Rutqvist LE, Mattsson A: Cardiac and thromboembolic morbidity among
postmenopausal women with early stage breast cancer in a randomized trial
of adjuvant tamoxifen. The Stockholm Breast Cancer Study Group. J Natl
Cancer Inst 85:1398-1406, 1993.
7. Killackey MA, Hakes TB, Pierce VK: Endometrial adenocarcinoma in
breast cancer patients receiving antiestrogens. Cancer Treat Rep 69:237-238,
8. Assikis VJ, Neven P, Jordan VC, et al: A realistic clinical perspective
of tamoxifen and endometrial carcinogenesis. Eur J Cancer Part A 32A:1464-1476,
9. Malfetano J: Tamoxifen-associated endometrial carcinoma in postmenopausal
breast cancer patients. Gynecol Oncol 39: 82-84, 1990.
10. Magriples U, Naftolin F, Schwartz PE, et al: High-grade endometrial
carcinoma in tamoxifen-treated breast cancer patients. J Clin Oncol 11:485-490,
11. National Cancer Institute: SEER Cancer Statistics Review 1973-1990,
Document #93-2789. Bethesda, Maryland, National Cancer Institute, 1993.
12. Fisher B, Costantino JP, Redmond CK, et al: Endometrial cancer in
tamoxifen-treated breast cancer patients: Findings from the NSABP B-14.
J Natl Cancer Inst 86:527-537, 1994.
13. Early Breast Cancer Trialists' Collaborative Group (EBCTCG): Systemic
treatment of early breast cancer by hormonal,cytotoxic,or immune therapy.
Lancet 339:1-15, 71-85, 1992.