Response of advanced breast cancer to total endocrine ablation after exacerbation on tamoxifen: results in seven patients and possible mechanism of action

Usage of tamoxifen in the treatment of advanced breast cancer is increasing and is advocated by some authors as primary therapy in all estrogen receptor positive cancer patients. Tamoxifen is an incomplete estrogen antagonist with partial estrogen agonist activity as well. Tamoxifen-induced exacerbation of breast cancer ("tamoxifen flare") is reported to occur in 4-20% or more of treated patients. Management of this condition has varied from stopping treatment to continued administration or reinstitution of tamoxifen after flare symptoms subside. Responses have occurred in some patients so treated, although the remissions do not appear durable. The seven patients with advanced breast cancer in this report experienced disease exacerbation with tamoxifen therapy. Endocrine ablation afforded all patients excellent pain relief and disease control with prolonged survival in six of the seven. There have been no studies directly examining the disease course in flare patients continuing on tamoxifen. Persistence in treating these patients with an incomplete antagonist-agonist may deprive them of full survival benefit possible through ablative procedures when used in sequential treatment.     

Tumor 'flare' hypercalcemia--an additional indication for bisphosphonates?

The most serious, potentially life-threatening manifestation of 'flare' is hypercalcemia, registered in 4-5% of breast cancer patients with bone metastases, usually during the first few weeks of tamoxifen treatment. There are no specific treatment recommendations for flare hypercalcemia, except tamoxifen withdrawal. There are no reports on the use of bisphosphonates in the treatment of flare hypercalcemia. Among 87 hypercalcemic patients with metastatic breast cancer observed during a 7-year period, 10 patients had tamoxifen-induced hypercalcemia. Diagnosis of flare hypercalcemia was based on the normal pretreatment values of serum calcium and the development of hypercalcemia within a maximum of 6 weeks of hormonal drug initiation. The median time from hormonal drug initiation to flare hypercalcemia was 14 days, the median duration 8.5 days, and the median calcium level was 3.09 mmol/l (range 2.79-4.46 mmol/l). All patients were treated with hydration, and 7 patients with calcium levels above 3.0 mmol/l were also treated with disodium pamidronate in various single doses (30-90 mg/24 h). Normocalcemia was achieved in all patients, and tamoxifen was continued without relapse of hypercalcemia. Median survival was 177 days (range 12-570 days). It seems that the use of bisphosphonates in the treatment of flare hypercalcemia could allow safe readministration of tamoxifen and prevent premature and unjustified tamoxifen discontinuation. Flare hypercalcemia might represent one more indication for the use of bisphosphonates.     

Tamoxifen: catalyst for the change to targeted therapy

In the early 1970s, a failed post-coital contraceptive, ICI 46,474, was reinvented as tamoxifen, the first targeted therapy for breast cancer. A cluster of papers published in the European Journal of Cancer described the idea of targeting tamoxifen to patients with oestrogen receptor positive tumours, and proposed the strategic value of using long-term tamoxifen therapy in an adjuvant setting with a consideration of the antitumour properties of the hydroxylated metabolites of tamoxifen. At the time, these laboratory results were slow to be embraced by the clinical community. Today, it is estimated that hundreds of thousands of breast cancer patients are alive today because of targeted long-term adjuvant tamoxifen therapy. Additionally, the first laboratory studies for the use of tamoxifen as a chemopreventive were published. Eventually, the worth of tamoxifen was tested as a chemopreventive and the drug is now known to have an excellent risk benefit ratio in high risk pre-menopausal women. Overall, the rigorous investigation of the pharmacology of tamoxifen facilitated tamoxifen's ubiquitous use for the targeted treatment of breast cancer, chemoprevention and pioneered the exploration of selective oestrogen receptor modulators (SERMs). This new concept subsequently heralded the development of raloxifene, a failed breast cancer drug, for the prevention of osteoporosis and breast cancer without the troublesome side-effect of endometrial cancer noted in post-menopausal women who take tamoxifen. Currently, the pharmaceutical industry is exploiting the SERM concept for all members of the nuclear receptor superfamily so that medicines can now be developed for diseases once thought impossible.     

Low-dose estrogen therapy to reverse acquired antihormonal resistance in the treatment of breast cancer

Estrogen is a potent stimulus for growth in its target organs: the uterus, vagina, and some estrogen receptor-positive breast cancers. However, estrogen is also able to control menopausal symptoms and maintain bone density in postmenopausal women. Until recently, there was also believed to be a link between estrogen and the prevention of cardiovascular disease. For these reasons, hormone replacement therapy (HRT) with an orally active estrogen and progesterone has been used routinely for more than 50 years to maintain physiologic homeostasis after menopause. Not surprisingly, HRT increases the risk of developing breast cancer. The link between estrogen and breast cancer growth served as the incentive to develop long-term tamoxifen therapy and, subsequently, the aromatase inhibitors (AIs) as successful "anti-estrogenic" treatments. Unfortunately, the consequence of exhaustive therapy is drug resistance. Laboratory studies have defined the evolution of tumor drug resistance to tamoxifen, raloxifene (used for breast and osteoporosis chemoprevention), and the AIs. Remarkably, the long-term exposure of breast cancers to antihormonal therapy also exposes a vulnerability that is being exploited in the clinic. Years of antihormonal therapy alters the cellular response mechanism to estrogen. Normally, estrogen is classified as a survival signal in breast cancer, but in sensitive antihormone-resistant cells, estrogen induces apoptosis. When resistant cells are killed, antihormonal therapy is once again effective. This new targeted approach to the treatment of metastatic breast cancer could open the door to novel approaches to treatment with drug combinations.     

Aromatase inhibitors for treatment of postmenopausal patients with breast cancer

The third generation of aromatase inhibitors and inactivators, such as anastrozole (Arimidex), letrozole (Femara) and exemestane (Aromasin), have become available for treatment of postmenopausal breast cancer patients. Several clinical trials have demonstrated that these new drugs can achieve better treatment results than megestrol acetate (Megace) and may replace tamoxifen for the first-line hormonal therapy for metastatic breast cancer patients. In fact, these drugs are now used in many hospitals and clinics for patients with metastatic breast cancer who were previously given tamoxifen as adjuvant treatment. However, the primary concern is whether they can be used as first-line agents for adjuvant treatment of primary breast cancer or are suitable for breast cancer prevention in view of possible adverse side effects. Recently, the Arimidex and Tamoxifen Alone or in Combination trial demonstrated the superiority in terms of disease-free survival of anastrozole over tamoxifen in adjuvant use for postmenopausal patients with Stage I and II primary breast cancer. The results of this report indicate the potential of anastrozole as an alternative drug in the adjuvant setting, although the mean follow-up time is so far only 47 months. Additional data regarding survival resulting from comparative trials of letrozole and tamoxifen and of exemestane and tamoxifen are expected to be available in a few years. However, limited information is available regarding adverse events caused by long-term administration of aromatase inhibitors. Longer follow-up is needed to determine the efficacy and safety of these new aromatase inhibitors when used for adjuvant treatment of postmenopausal patients with breast cancer.     

Tamoxifen flare in advanced endometrial carcinoma

Tamoxifen citrate has recently been shown to be effective palliative therapy in advanced endometrial carcinoma. Flare reactions from tamoxifen are well known in treatment of metastatic breast carcinoma and are not an indication for stopping therapy. We report a patient being treated with tamoxifen for advanced endometrial cancer who developed acute abdominal pain as a manifestation of a flare reaction and the significance of this observation.     

Current status of endocrine therapy for breast cancer

Endocrine therapy is usually indicated prior to chemotherapy as the first line therapy for metastatic breast cancer patients because of its milder toxicity. Patients who respond to a first-line endocrine therapy have a high chance of responding to a second-line endocrine therapy, and thus the responders to a first-line endocrine therapy would better be treated with second or third-line endocrine therapy. In the adjuvant setting, tamoxifen (antiestrogen) has been proven to improve the prognosis of both pre- and postmenopausal estrogen receptor positive breast cancer patients, and goserelin (LH-RH agonist) has been proven to improve prognosis in premenopausal women comparable to chemotherapy (CMF). Very recently, preliminary results have indicated that anastrozole (aromatase inhibitor) is superior to tamoxifen as adjuvant treatment for estrogen receptor positive postmenopausal breast cancer patients. In addition, the recent success of tamoxifen in a chemoprevention trial seems to have ushered in a new era wherein prevention of breast cancer is much more emphasized than treatment of established breast cancer.     

Tamoxifen in premenopausal patients with metastatic breast cancer: a review

The antiestrogen tamoxifen is the most widely used hormonal therapy for breast cancer. The drug exerts its antiproliferative effects primarily through estrogen receptor (ER)-mediated mechanisms, although other cellular actions may augment tumor inhibition. Clinically, tamoxifen has been less well studied in premenopausal than in postmenopausal patients. The drug has complex endocrine effects that are dependent on the treatment duration and dose, menopausal status, and target organ. In postmenopausal women receiving tamoxifen, serum estrogen levels remain low, and the normally elevated gonadotropin levels decrease. In contrast, serum estrogen levels are strikingly elevated in many premenopausal women, and gonadotropin concentrations are either unchanged or slightly increased. Large systematic trials in metastatic breast cancer have established tamoxifen as the recommended hormonal therapy for postmenopausal women with ER-positive tumors. Tamoxifen is also an active agent for premenopausal metastatic disease, and response rates are comparable to those reported for oophorectomy. Clinical experience with tamoxifen in this younger age group, however, is more limited. Few premenopausal women (less than 400) have been included in phase II and phase III trials. Two randomized trials (total of 160 patients) comparing oophorectomy with tamoxifen do not definitively establish therapeutic equivalence, and a survival advantage for either treatment cannot be excluded. Many questions remain concerning the appropriate role for tamoxifen in premenopausal patients. Still, tamoxifen has an attractive toxicity profile, and it offers a favorable therapeutic alternative for premenopausal women with ER-positive metastatic breast cancer who wish to avoid surgical or radiation castration.     

Risk of endometrial hyperplasia and carcinoma in breast cancer patients receiving adjuvant tamoxifen

The antiestrogen drug tamoxifen, which is widely used in adjuvant hormone therapy of breast cancer, presents certain risk of causing hyperplasia and endometrial carcinoma. Our clinical data on 1,969 breast cancer patients (stage I-III) (tamoxifen--947; control--1,022) showed a double rise in endometrial carcinoma risk in cases receiving hormone therapy. Endometrial carcinoma incidence in tamoxifen-treated patients was 3% while in the untreated ones--1.6% (p < 0.05). According to the endometrial tissue study in 439 breast cancer patients, proliferative effect of tamoxifen in the form of endometrial hyperplasia was 5--6 times in tamoxifen users. Meanwhile, endometrial carcinoma and hyperplasia risk increased during a much longer exposure to tamoxifen and in combination with such factors as obesity, diabetes mellitus, uterine myoma and estrogen-type colpocytological response. Hence, breast cancer patients need to undergo dynamic follow-up of the endometrium including ultrasonic examination of the small-pelvis organs and cytological study of ecto- and endocervical smears and endometrial aspirates.     

Molecular mechanisms of antiestrogen action in breast cancer

The success of antiestrogen therapy to treat all stages of breast cancer, and the evaluation of tamoxifen as a preventive for breast cancer in normal women, have focused attention on the molecular mechanisms of antiestrogen action and mechanisms of drug resistance. The overall goal of research is to enhance current therapies and to develop new approaches for breast cancer treatment and prevention. Recent studies show that tamoxifen and the new pure antiestrogens appear to have different mechanisms of action: tamoxifen and related compounds cause a change in the folding of the steroid binding domain that prevents gene activation whereas the pure antiestrogens cause a reduced interaction at response elements and cause a rapid loss of receptor complexes. Tamoxifen treatment produces changes in the cellular and circulating levels of growth factors that could influence both receptor negative or receptor positive tumor growth and the metastatic potential of a tumor. These events may explain the survival advantage observed with tamoxifen therapy. However, the current therapeutic challenge is to avoid drug resistance during long-term tamoxifen therapy. Numerous explanations for drug resistance to tamoxifen have been suggested, including elevated estrogen levels, increased tumor antiestrogen binding sites, receptor mutations, and impaired signal transduction. However, it is probable that multiple mechanisms evolve to facilitate tumor survival. Most importantly, current research is examining mechanisms responsible for the beneficial actions of tamoxifen on bones and lipids as well as the potentially deleterious effects of tamoxifen on liver and endometrial carcinogenesis and retinopathy. The urgent need to understand antiestrogenic drug mechanisms and toxicity is being facilitated by the application of the technology developed for basic molecular biology.     

Choosing early adjuvant therapy for postmenopausal women with hormone-sensitive breast cancer: Aromatase inhibitors versus tamoxifen

Aims

The aromatase inhibitors (AIs) anastrozole, exemestane, and letrozole have demonstrated superior disease-free survival (DFS) over tamoxifen in several trials. As the choice of adjuvant endocrine treatment for early breast cancer (EBC) is evolving from tamoxifen to the AIs, this review compares the AIs with tamoxifen to help surgeons choose a treatment plan that provides the greatest reduction of recurrence risk for their patients.

Methods

MEDLINE was searched to identify relevant literature on the adjuvant use of tamoxifen and AIs in EBC.

Results

Despite the use of adjuvant tamoxifen, recurrence is a persistent threat to women with hormone-sensitive EBC. Trials of the AIs versus tamoxifen have established that patients benefit from longer DFS, and in some cases distant DFS, after the use of an AI as initial adjuvant therapy, as switch therapy following 2–3 years of tamoxifen, or as extended adjuvant therapy following 5 years of tamoxifen. The AIs are well tolerated, with a different safety profile than that of tamoxifen in all these settings. Trials addressing the optimal regimen and treatment duration for AIs are also underway.

Conclusions

The advantage in DFS associated with AIs over tamoxifen use should prompt physicians and patients to consider the use of an AI as the initial adjuvant endocrine therapy or, alternatively, switching patients who currently take tamoxifen to an AI for the remainder of adjuvant endocrine therapy. Prolonging the period of adjuvant therapy with letrozole after 5 years of tamoxifen reduces recurrence and is associated with a survival advantage in node-positive patients.     

“Studies on the estrogen receptor in breast cancer” — 20 years as a target for the treatment and prevention of cancer

Summary In 1973, McGuire and Chamness (In: O'Malley BW and Means AR (eds) Receptors for Reproductive Hormones, Plenum Press) summarized their work on the estrogen receptor in animal and human breast tumors, and in so doing described a target for therapeutic intervention. At that time there were no clinically useful antiestrogens, but the subsequent development of tamoxifen for breast cancer therapy has revolutionized the approach to treatment. Long-term adjuvant tamoxifen adjuvant therapy (i.e. greater than one year) has proven efficacy to enhance the survival of breast cancer patients. In addition, because there is an associated 40% decrease in contralateral breast cancer during adjuvant tamoxifen therapy and tamoxifen maintains bone density and reduces fatal myocardial infarction, clinical trials to test the worth of tamoxifen as a preventive for breast cancer in high risk women have started in the United States, United Kingdom, and Italy. Initial concerns that long-term tamoxifen causes endometrial cancer have been placed in perspective and analyzed by a review of the literature. Tamoxifen only doubles the normal risk of detecting endometrial cancer, (i.e. to 2 per 1,000 tamoxifen-treated women per year), and 80% of these cases are early stage, good prognosis disease. Annual gynecological examinations and education are essential to provide reassurance for patients.The success of tamoxifen has encouraged the development of new antiestrogens to exploit the estrogen receptor as a therapeutic target. Droloxifene and TAT-59 mimic the metabolite 4-hydroxytamoxifen in having a high affinity for the estrogen receptor (Jordan et al, J Endocrinol 75:305, 1977). These drugs appear to have a pharmacological profile similar to tamoxifen. In contrast, the new pure antiestrogens have a distinct mechanism of action and will be valuable either as a first line therapy for advanced breast cancer or as a second line endocrine therapy after the failure of long-term adjuvant tamoxifen therapy.Finally, a new strategy is being developed to exploit the target site specific action of antiestrogens. Raloxifene, an antiestrogen with high affinity for the estrogen receptor but only weak estrogenicity for the uterus, prevents rat mammary tumorigenesis and maintains bone density. The drug is to be evaluated as a treatment for osteoporosis, but may also prevent the development of breast and endometrial cancer in a broad group of treated subjects.The identification of the estrogen receptor as a target for therapeutic opportunities has proved to be extremely beneficial for the control of breast cancer and has the added potential to control osteoporosis and coronary heart disease in women.Presented at the 17th Annual San Antonio Breast Cancer Symposium. The William L. McGuire Memorial Lectures are sponsored by an educational grant from Wellcome Oncology.     

Exemestane in breast cancer: current status and future directions

Exemestane is a novel, potent, and specific third-generation aromatase inactivator developed for breast can-cer therapy. The drug is effective in patients with metastatic disease failing tamoxifen alone or tamoxifen followed by megestrol acetate or a nonsteroidal aromatase inhibitor. In a phase III study, exemestane was superior to megestrol acetate in overall survival, time to tumor progression, and time to treatment failure in women with metastatic disease who experienced failure of tamoxifen. Preliminary evidence suggests activity to exemestane exceeds that obtained with tamoxifen as first-line treatment. Two studies are comparing sequential treatment with tamoxifen followed by exemestane to tamoxifen monotherapy in the adjuvant setting. A third study is comparing the toxicity profile of exemestane with that of placebo in patients with early breast cancer who are at low risk of relapse. The findings from these studies will determine the role of exemestane in early breast cancer and lay the foundation for assessing its potential role in breast cancer prevention.     

Long-term adjuvant tamoxifen therapy for breast cancer

Tamoxifen (ICI46,474) is a competitive inhibitor of estrogen action which has found ubiquitous application in the treatment of breast cancer. The drug is the front line endocrine therapy for breast cancer and is the proven treatment of choice for the adjuvant therapy of postmenopausal women with node-positive disease. Tamoxifen is available for the treatment of premenopausal patients with advanced disease, and is being evaluated in clinical trials as an adjuvant therapy for premenopausal patients with either node-positive or node-negative disease. Laboratory studies demonstrate that tamoxifen is a tumoristatic agent and long-term treatment strategies (chemosuppression) should be considered to apply the antiestrogen to its maximal therapeutic advantage. Optimal therapy with tamoxifen may also be achieved by treatment strategies to lower circulating estrogen levels in the premenopausal patient.Tamoxifen is a well tolerated drug, and long-term therapy does not appear to induce metabolic tolerance. Concerns about premature osteoporosis or cardiovascular disease appear to be unfounded because tamoxifen has an appropriate level of target site-directed estrogenic activity. Isolated reports about the growth or appearance of endometrial carcinoma during long-term adjuvant tamoxifen therapy must be balanced against the risks of withholding treatment to patients with a fatal disease.     

Overview from the International Conference on Long-Term Tamoxifen Therapy for Breast Cancer.

The development of tamoxifen therapy to treat selected patients, with all stages of breast cancer, has provided the clinical community with an efficacious and safe drug for long-term therapy. Issues of safety are under constant review, but justified concerns about high doses of tamoxifen acting as a promoter of liver cancer in rats or as a promoter of endometrial cancer in women have not, as yet, proved to be of clinical relevance. The situation will continue to be reviewed during the development of the prevention studies in Europe and the United States because an improvement in women's health is the ultimate goal of these programs. The hallmark for the successful development of tamoxifen has been the close cooperation between the laboratory and the clinic. The clinical strategy of long-term tamoxifen therapy is a direct application of a laboratory concept. Furthermore, potential problems in the clinic have been identified in the laboratory, and the clinical community has responded quickly to evaluate the real risks to the patient population. This close cooperation will continue. Issues of drug resistance, new antiestrogen development, and the application of the knowledge about steroid receptors to develop targeted gene therapies are being addressed so that additional treatment approaches for breast cancer will be in place by the turn of the century.     

Metabolic flare: indicator of hormone responsiveness in advanced breast cancer.

PURPOSE: The purpose of this study was to investigate whether positron emission tomography (PET) with the glucose analog [(18)F]fluorodeoxyglucose (FDG) and the estrogen analog 16 alpha-[(18)F]fluoroestradiol-17 beta (FES), performed before and after treatment with tamoxifen, could be used to detect hormone-induced changes in tumor metabolism (metabolic flare) and changes in available levels of estrogen receptor (ER). In addition, we investigated whether these PET findings would predict hormonally responsive breast cancer. PATIENTS AND METHODS: Forty women with biopsy-proved advanced ER-positive (ER(+)) breast cancer underwent PET with FDG and FES before and 7 to 10 days after initiation of tamoxifen therapy; 70 lesions were evaluated. Tumor FDG and FES uptake were assessed semiquantitatively by the standardized uptake value (SUV) method. The PET results were correlated with response to hormonal therapy. RESULTS: In the responders, the tumor FDG uptake increased after tamoxifen by 28.4% +/- 23.3% (mean +/- SD); only five of these patients had evidence of a clinical flare reaction. In nonresponders, there was no significant change in tumor FDG uptake from baseline (mean change, 10.1% +/- 16.2%; P =.0002 v responders). Lesions of responders had higher baseline FES uptake (SUV, 4.3 +/- 2.4) than those of nonresponders (SUV, 1.8 +/- 1.3; P =.0007). All patients had evidence of blockade of the tumor ERs 7 to 10 days after initiation of tamoxifen therapy; however, the degree of ER blockade was greater in the responders (mean percentage decrease, 54.8% +/- 14.2%) than in the nonresponders (mean percentage decrease, 19.4% +/- 17.3%; P =.0003). CONCLUSION: The functional status of tumor ERs can be characterized in vivo by PET with FDG and FES. The results of PET are predictive of responsiveness to tamoxifen therapy in patients with advanced ER(+) breast cancer.     

Role of adjuvant endocrine therapy in early-stage breast cancer

The value of adjuvant endocrine therapy in saving lives of women with estrogen receptor-positive (ER(+)) early-stage breast cancer cannot be disputed. Tamoxifen has proven to be effective in improving relapse-free and overall survival in both pre- and postmenopausal women with ER(+) early-stage breast cancer. In the meta-analysis of the Early Breast Cancer Trialists' Collaborative Group, the proportional reduction in recurrence and mortality for 5 years of tamoxifen therapy was 50% and 28% respectively for patients with ER(+) tumors. These reductions in recurrence and mortality were similar in both lymph node-negative (N(-)) and lymph node-positive (N(+)) patients and translate to an absolute improvement in 10-year survival of approximately 11% in N(+) patients and 6% in N(-) patients. Current data suggest that about 5 years of tamoxifen therapy is the optimal duration of treatment. For women with ER(-)/progesterone receptor-negative (PR(-)) tumors, tamoxifen does not lower the risk of distant metastases or improve survival. In ER(+) patients, the addition of tamoxifen to chemotherapy further lowers the risk of recurrence by about 30% to 40% when compared to chemotherapy alone. In premenopausal women with ER(+) breast cancer, ovarian ablation has proven to be as effective as chemotherapy in improving both relapse-free and overall survival and the potential additive role of ovarian ablation to chemotherapy and/or tamoxifen is presently being explored in clinical trials. The combination of tamoxifen and ovarian ablation is currently being tested and may be superior to tamoxifen alone. In addition, newer, more effective, and less toxic aromatase inhibitors are also being evaluated in clinical trials in the adjuvant setting and have great promise. "Pure" antiestrogens or selective estrogen receptor down-regulators (SERDs) will be studied in adjuvant clinical trials in the near future. Recent data also suggest that molecular markers such as HER-2/neu may predict the response to endocrine therapy, and other predictive factors are currently being evaluated. Lastly, there is renewed interest in neoadjuvant endocrine therapy, a treatment option that may select those patients with early-stage breast cancer most likely to benefit from endocrine therapy.     

Current status of endocrine treatment of carcinoma of the breast

Sequential administration of endocrine therapies can result in objective remission in a significant fraction of patients with metastatic breast cancer. Combined hormonal therapies and combined hormonochemotherapies have not resulted in better results than the sequential administration of these same therapies. Tamoxifen (an antiestrogen) given as an initial therapy results in local control of the disease in a significant fraction of patients with locally advanced breast cancer who are not candidates for cytotoxic therapy. Tamoxifen as an adjuvant therapy for operable breast cancer prolongs disease-free survival and reduces mortality in patients greater than 50 yr of age with higher estrogen receptor concentrations. The role of tamoxifen as adjuvant therapy for patients less than 50 yr of age remains unclear. Also, adjuvant tamoxifen in combination with cytotoxic drugs has not produced superior results, and the duration of adjuvant tamoxifen therapy remains to be determined. Experimental data suggest prolonged administration of tamoxifen may be needed to control micrometastases.     

Laboratory models of breast and endometrial cancer to develop strategies for antiestrogen therapy

Laboratory models for breast and endometrial cancer have had an enormous impact on the clinical development of antiestrogens. Results from the DMBA-induced rat mammary cancer model has provided the scientific principles required to evaluate long-term adjuvant tamoxifen therapy. Similarly, the athymic mouse model allowed the identification of clinically relevant mechanisms of drug resistance to tamoxifen and a model system to test new agents for cross resistance. Additionally, the endometrial cancer model has allowed the identification of agents that cause a slight increase in the risk of endometrial cancer long before the data would have be available from clinical studies. However, it should be stressed that this model is really only relevant for agents to be tested as preventives in normal women. The risks of developing endometrial cancer during tamoxifen therapy are slight compared with the survival benefit in controlling breast cancer.Finally the discovery of the carcinogenic potential of tamoxifen in the rat liver, 20 years after it was first introduced into clinical practice, raises an interesting issue. If the studies of liver carcinogenicity had been completed and published in the early 1970's there would be no tamoxifen and tens of thousands of women with breast cancer would have died prematurely. In fact there would have been no incentive to develop new agents as alternatives to tamoxifen or following tamoxifen failure. Most importantly, we would not have any knowledge about the target-site or selective actions of antiestrogens. All the current interest in selective estrogen receptor modulators (SERMs) is based on the huge clinical data base obtained by studying tamoxifen. The success of tamoxifen as an agent that preserves bone density, lowers cholesterol and prevents contralateral breast cancer(43) has become a classic example of a multimechanistic drug. These concepts have acted as a catalyst to develop new agents for new applications. The laboratory studies of raloxifene(44-46)) provided the scientific rationale for the use of raloxifene as a preventive for osteoporosis(47)) but with the goal of preventing breast cancer in post-menopausal women(48,49)) (Fig 5). It is clear that the close collaboration between laboratory and clinical research has revolutionized the prospects for women's health care in the 21st century.