Osteopenia and osteoporosis in women with breast cancer

Osteopenia and osteoporosis are prevalent in women. Epidemiologic studies show that the risk of breast cancer is greater in postmenopausal women with higher bone mineral density (BMD). Standard treatments for breast cancer such as adjuvant chemotherapy or hormonal therapy can increase bone loss, and hence may increase the risk of osteoporosis. Premenopausal women treated with standard adjuvant chemotherapy frequently develop permanent ovarian failure, or early menopause. Ovarian failure is associated with accelerated bone loss, and bisphosphonates may mitigate this bone loss in women treated with adjuvant chemotherapy. Tamoxifen preserves BMD in postmenopausal women; however, in premenopausal women tamoxifen may increase bone loss. Anastrazole, an aromatase inhibitor, is approved for adjuvant treatment of postmenopausal women with early-stage, estrogen receptor-positive breast cancer. With a follow-up duration of less than 5 years, anastrazole-treated women experience increased fractures relative to those treated with tamoxifen. The management of osteopenia and osteoporosis in women with breast cancer generally does not differ from women without breast cancer. Adequate dietary calcium and vitamin D intake, encouraging weight-bearing exercise, and counseling about the relationship between smoking and alcohol and bone loss are all prudent recommendations for overall health and may lessen bone loss and the risk of subsequent osteoporosis. BMD should be measured in women with chemotherapy-induced ovarian failure, and in those on aromatase inhibitors. Bisphosphonates reduce the bone loss associated with chemotherapy-induced ovarian failure, and clinical trials evaluating third-generation bisphosphonates in women with chemotherapy-induced ovarian failure are underway. As many women with breast cancer will be long-term survivors, increasing recognition of maintaining skeletal health is important.     

Skeletal health in postmenopausal survivors of early breast cancer

Estrogen plays an important role in the skeletal health of all women. Many therapies used in the treatment of breast cancer reduce estrogen levels and have the potential to affect bone negatively by increasing the risk of osteoporosis and associated bone fractures. The long-term effects of systemic endocrine therapy on bone, therefore, are an important consideration in the adjuvant setting. Tamoxifen has been shown to have a moderate protective effect on postmenopausal bone due to its partial estrogen agonist activity; however, its long-term use is potentially associated with negative side effects, such as an increased risk of thromboembolic disease and endometrial cancer. Newer agents, the third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, for example, do not possess estrogen agonist effects and have improved breast cancer outcomes when compared to the standard 5 years of tamoxifen. However, patients treated with adjuvant AIs have been shown to have an increased incidence of osteoporosis and osteoporotic fractures. In order to select the optimal adjuvant therapy for each patient, it is important to assess the overall risk:benefit ratio for each endocrine strategy. All postmenopausal women should follow published guidelines to assess the risk of osteoporosis and, where appropriate, they should receive bone mineral density monitoring. Postmenopausal women with breast cancer who are at increased risk of osteoporotic fracture should be identified and managed with appropriate nonpharmacologic and pharmacologic measures.     

Choosing between an aromatase inhibitor and tamoxifen in the adjuvant setting

PURPOSE OF REVIEW: Approximately three-quarters of all invasive breast tumors are estrogen and/or progesterone receptor-positive. The selective estrogen receptor modulator tamoxifen has been the preferred endocrine therapy for almost four decades. One of the most significant advances in endocrine therapy for women after menopause with early breast cancer is the introduction of third-generation aromatase inhibitors as an alternative or as an additional treatment to tamoxifen therapy. In making a choice between the use of an aromatase inhibitor or tamoxifen in the adjuvant setting, a careful analysis of both the efficacy data and toxicity profiles of each drug is essential. RECENT FINDINGS: In the adjuvant setting, three major randomized controlled trials have reported on the use of three different aromatase inhibitors for women after menopause with breast cancer. In all of these trials, the third-generation aromatase inhibitors demonstrated significantly improved disease-free survival, either compared with tamoxifen as an initial adjuvant hormonal therapy, or when aromatase inhibitors were given sequentially after tamoxifen therapy. The toxicity data suggest that bone loss, increased fracture rates, and other musculoskeletal disorders are the most serious side effects associated with the use of aromatase inhibitors. Toxicities commonly associated with tamoxifen therapy such as thromboembolic events and endometrial abnormalities are reduced in patients receiving aromatase inhibitors, however. SUMMARY: The present data demonstrate the improved efficacy achieved with third-generation aromatase inhibitors compared with tamoxifen and support the use of these agents in the adjuvant setting. The optimal treatment strategy for whether these agents should be given in place of tamoxifen or as part of a sequential treatment has yet to be defined, however. Moreover, to be able to optimize treatment with aromatase inhibitors, it is imperative to develop interventions to prevent or alleviate treatment related side effects.     

Guidance for the management of breast cancer treatment-induced bone loss: a consensus position statement from a UK Expert Group

In postmenopausal women, the use of aromatase inhibitors increases bone turnover and induces bone loss at sites rich in trabecular bone at an average rate of 1-3% per year leading to an increase in fracture incidence compared to that seen during tamoxifen use. The bone loss is much more marked in young women with treatment-induced ovarian suppression followed by aromatase inhibitor therapy (average 7-8% per annum). Pre-treatment with tamoxifen for 2-5 years may reduce the clinical significance of the adverse bone effects associated with aromatase inhibitors, particularly if this leads to a shortening in the duration of exposure to an aromatase inhibitor. However, skeletal status should still be assessed at the commencement of aromatase inhibitor therapy. The rate of bone loss in women who experience a premature menopause before the age of 45 or are receiving ovarian suppression therapy is accelerated by the concomitant use of aromatase inhibitors. These patients are considered to be at high risk of clinically important bone loss and should have a baseline dual energy X-ray absorptiometry (DXA) assessment of bone mineral density (BMD). Randomised clinical trials in postmenopausal women indicate that bisphosphonates prevent the bone loss and accelerated bone turnover associated with aromatase inhibitor therapy and are a promising strategy for the prevention and treatment of osteoporosis in this setting. Treatment initiation recommendations are based on a combination of risk factors for osteoporotic fracture and BMD levels. Bisphosphonates, along with a healthy lifestyle and adequate intake of calcium and vitamin D are the treatments of choice to prevent bone loss. Due to the rate of bone loss associated with breast cancer treatments, and uncertainties about the interaction between aromatase inhibitor use and BMD for fracture risk, the threshold for intervention has been set at a higher level than that generally recommended for postmenopausal osteoporosis. Management recommendations have been summarised in two algorithms, one for women experiencing a premature menopause and the other for postmenopausal women requiring adjuvant aromatase inhibitor therapy.     

Bone loss and the aromatase inhibitors

The increasing use of systemic adjuvant therapies has considerably improved the prognosis from early breast cancer. However, some of these therapies affect bone metabolism, resulting in osteoporosis. Aromatase inhibitors lower circulating oestrogen levels to almost unrecordable levels in postmenopausal women, predisposing them to bone loss with an increase in fracture risk. Ongoing clinical trials are favouring the use of the aromatase inhibitors over tamoxifen and this may advocate greater use of these drugs in the future. Strategies for the identification and management of treatment-induced bone loss are currently being defined.     

Strategies for the prevention of treatment-related bone loss in women receiving adjuvant hormonal therapy

More than 220,000 women will be diagnosed with breast cancer this year, and approximately 75% of these women will be long-term survivors of this disease. Survival has improved largely because of advances in adjuvant hormone therapy and chemotherapy, as well as early detection strategies. Because most women will receive adjuvant treatment, and the majority will survive cancer, it is increasingly important to understand the resultant toxicities and to devise monitoring and treatment strategies to avoid adverse long-term effects. Loss of bone mineral density leading to osteoporosis and increased risk of fracture as well as other morbidities is a well known complication of estrogen suppression associated with use of aromatase inhibitors (AIs) in postmenopausal women, and ovarian suppression with GnRH agonists or chemotherapy in premenopausal women. Hormone receptor positivity is increasingly frequent with increasing patient age, so that a large number of women already at risk for osteopenia associated with menopause are at risk for further bone loss caused by adjuvant hormone therapy with AIs. This article will review data on bone mineral density loss and risk of fracture in the large, randomized phase III trials comparing tamoxifen to AIs using the upfront, switching or extended hormone therapy approach. Data from prophylactic bisphosphonate intervention trials in both post- and premenopausal women will be discussed. Ongoing trials are described.     

American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004.

PURPOSE: To update the 2003 American Society of Clinical Oncology technology assessment on adjuvant use of aromatase inhibitors. RECOMMENDATIONS: Based on results from multiple large randomized trials, adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer should include an aromatase inhibitor in order to lower the risk of tumor recurrence. Neither the optimal timing nor duration of aromatase inhibitor therapy is established. Aromatase inhibitors are appropriate as initial treatment for women with contraindications to tamoxifen. For all other postmenopausal women, treatment options include 5 years of aromatase inhibitors treatment or sequential therapy consisting of tamoxifen (for either 2 to 3 years or 5 years) followed by aromatase inhibitors for 2 to 3, or 5 years. Patients intolerant of aromatase inhibitors should receive tamoxifen. There are no data on the use of tamoxifen after an aromatase inhibitor in the adjuvant setting. Women with hormone receptor-negative tumors should not receive adjuvant endocrine therapy. The role of other biomarkers such as progesterone receptor and HER2 status in selecting optimal endocrine therapy remains controversial. Aromatase inhibitors are contraindicated in premenopausal women; there are limited data concerning their role in women with treatment-related amenorrhea. The side effect profiles of tamoxifen and aromatase inhibitors differ. The late consequences of aromatase inhibitor therapy, including osteoporosis, are not well characterized. CONCLUSION: The Panel believes that optimal adjuvant hormonal therapy for a postmenopausal woman with receptor-positive breast cancer includes an aromatase inhibitor as initial therapy or after treatment with tamoxifen. Women with breast cancer and their physicians must weigh the risks and benefits of all therapeutic options.     

Strategies to prevent chemotherapy-induced bone loss in women with breast cancer

Treatment-induced osteoporosis is an increasing problem for women diagnosed with breast cancer. As more women receive adjuvant endocrine therapy and chemotherapy, and breast cancer survival improves, the impact of cancer treatment on bone health and the morbidity associated with chemotherapy-induced bone loss becomes more of a significant medical concern. Endocrine agents like aromatase inhibitors and luteinizing hormone-releasing hormone agonists decrease the production of ovarian and adrenal estrogens and are widely used in the adjuvant and metastatic settings for treatment of women with hormone receptor-positive breast cancer. Estrogen is important for bone health. It stimulates osteoblasts and maintains bone integrity. As bone density decreases, the risk of fracture increases. This can include fractures of the wrist, femur, and vertebrae. Several potent bisphosphonates have been developed to prevent or treat cancer treatment-induced bone loss.     

Current role and safety profile of aromatase inhibitors in early breast cancer

The current adjuvant therapy for breast cancer is in a continous progress; standard therapeutic strategies include the use of chemotherapy, molecular targeted drugs and hormonal agents, according to well-established prognostic and predictive factors. Among the hormonal drugs, for a long period tamoxifen has been the gold standard of adjuvant therapy in postmenopausal women with hormone receptor-positive (HR+) early breast cancer. In the last years an expanding use of aromatase inhibitors occurred in this subset of patients, because the third-generation class of these agents (anastrozole, letrozole and exemestane) showed to be more effective and safe than tamoxifen and are now recommended as the preferred hormonal approach to postmenopausal hormone-sensitive patients, according to national and international guidelines. Treatment choices with these agents include the use of an aromatase inhibitor as an upfront strategy for 5 years, as a sequential approach after 2–3 years of tamoxifen, or as an extended use after the classical 5 years of tamoxifen. The improved efficacy of aromatase inhibitors over tamoxifen has been largely demonstrated in terms of better disease-free survival, reductions in the occurrence of early distant metastasis as well as improvement of overall survival. Moreover, according to the optimal duration of therapy, presently it is not known whether aromatase inhibitor therapy, as tamoxifen, should be limited to 5 years. In terms of safety profile, the side effects of aromatase inhibitors, as compared with selective estrogen receptor modulators, are different, reflecting the specific mechanism of action of these drugs. There is strong evidence that aromatase inhibitors are well tolerated, with a lower incidence of gynecological symptoms (vaginal bleeding, discharge and endometrial neoplasia), venous thromboembolic events and hot flushes than tamoxifen. On the other hand, the use of aromatase inhibitors has been associated with loss of bone density, arthralgia, myalgia, and a negative effect on lipid metabolism and cardiovascular risk. More extensive and mature studies are necessary to well establish the safety of aromatase inhibitors when given to patients with breast cancer for a long time.     

Current role and safety profile of aromatase inhibitors in early breast cancer

The current adjuvant therapy for breast cancer is in a continous progress; standard therapeutic strategies include the use of chemotherapy, molecular targeted drugs and hormonal agents, according to well-established prognostic and predictive factors. Among the hormonal drugs, for a long period tamoxifen has been the gold standard of adjuvant therapy in postmenopausal women with hormone receptor-positive (HR+) early breast cancer. In the last years an expanding use of aromatase inhibitors occurred in this subset of patients, because the third-generation class of these agents (anastrozole, letrozole and exemestane) showed to be more effective and safe than tamoxifen and are now recommended as the preferred hormonal approach to postmenopausal hormone-sensitive patients, according to national and international guidelines. Treatment choices with these agents include the use of an aromatase inhibitor as an upfront strategy for 5 years, as a sequential approach after 2-3 years of tamoxifen, or as an extended use after the classical 5 years of tamoxifen. The improved efficacy of aromatase inhibitors over tamoxifen has been largely demonstrated in terms of better disease-free survival, reductions in the occurrence of early distant metastasis as well as improvement of overall survival. Moreover, according to the optimal duration of therapy, presently it is not known whether aromatase inhibitor therapy, as tamoxifen, should be limited to 5 years. In terms of safety profile, the side effects of aromatase inhibitors, as compared with selective estrogen receptor modulators, are different, reflecting the specific mechanism of action of these drugs. There is strong evidence that aromatase inhibitors are well tolerated, with a lower incidence of gynecological symptoms (vaginal bleeding, discharge and endometrial neoplasia), venous thromboembolic events and hot flushes than tamoxifen. On the other hand, the use of aromatase inhibitors has been associated with loss of bone density, arthralgia, myalgia, and a negative effect on lipid metabolism and cardiovascular risk. More extensive and mature studies are necessary to well establish the safety of aromatase inhibitors when given to patients with breast cancer for a long time.     

Appraising adjuvant aromatase inhibitor therapy

Tamoxifen, once the gold standard adjuvant endocrine therapy for early breast cancer, is being challenged by third-generation aromatase inhibitors (AIs) that have demonstrated improved disease-free survival in a variety of adjuvant settings for early breast cancer. Tamoxifen and AIs have different safety profiles, which should allow physicians to begin to individualize treatment based on a patient's comorbidities and risk factors. Because of its properties as a partial estrogen agonist, tamoxifen has a positive effect on serum lipids and may confer a cardioprotective benefit, as well as a beneficial effect on bone health. However, tamoxifen increases the risk for endometrial cancer and cerebrovascular/thromboembolic events. In comparison, the major side effect of AIs is increased bone loss, which may heighten the risk for osteoporotic fractures and bone pain. Because of their superior efficacy and manageable side effects, AIs are a cost-effective alternative to tamoxifen, and clinical guidelines now embrace AIs as appropriate adjuvant therapy for hormone-sensitive early breast cancer. The anticipated results of ongoing trials will provide further insights into the long-term safety and application of AI therapy in the adjuvant setting.     

Aromatase inhibitors in the treatment of early and advanced breast cancer

The third generation aromatase inhibitors anastrozole, exemestane, and letrozole have been compared with tamoxifen and other endocrine therapies in several studies in early and advanced breast cancer. These studies are reviewed in this report. Based on the available evidence, the panel recommends that adjuvant treatment with tamoxifen for 5 years should no longer be considered as the sole standard but that a third-generation aromatase inhibitor should be used either alone or in a sequence with tamoxifen in the adjuvant treatment of postmenopausal women with hormone-receptor-positive breast cancer. Third generation aromatase inhibitors may be considered as the first line therapy of hormone-receptor-positive advanced breast cancer in postmenopausal women, and they may also be used for preoperative therapy of breast cancer.     

Women and bone health: maximizing the benefits of aromatase inhibitor therapy

Postmenopausal women with early breast cancer (EBC) are already at risk for bone loss, osteoporosis and fracture as they age because of declining estrogen levels. Adjuvant hormonal therapy with aromatase inhibitors (AIs; e.g. letrozole, anastrozole, exemestane) can exacerbate this risk. All three AIs appear to have similar effects on bone, increasing bone turnover and fracture risk in postmenopausal women with EBC. Risk factors for bone loss can be used to assess fracture risk and the need for ongoing assessment and/or treatment in postmenopausal women receiving AIs for EBC. The concomitant, up-front use of intravenous bisphosphonate therapy, such as zoledronic acid, in combination with AIs can inhibit bone loss. In addition, a strong body of evidence suggests an anticancer activity of bisphosphonate therapy with zoledronic acid in EBC in both the pre- and postmenopausal adjuvant setting. Zoledronic acid thus provides a therapeutic option for postmenopausal women with EBC who may be at higher risk for bone loss while on AIs, allowing more patients to receive treatment with effective adjuvant hormonal therapy to prevent recurrence.     

Aromatase inhibitor-associated bone and musculoskeletal effects: new evidence defining etiology and strategies for management

Aromatase inhibitors are widely used as adjuvant therapy in postmenopausal women with hormone receptor-positive breast cancer. While the agents are associated with slightly improved survival outcomes when compared to tamoxifen alone, bone and musculoskeletal side effects are substantial and often lead to discontinuation of therapy. Ideally, the symptoms should be prevented or adequately treated. This review will focus on bone and musculoskeletal side effects of aromatase inhibitors, including osteoporosis, fractures, and arthralgias. Recent advances have been made in identifying potential mechanisms underlying these effects. Adequate management of symptoms may enhance patient adherence to therapy, thereby improving breast cancer-related outcomes.     

Aromatase inhibitor therapy: toxicities and management strategies in the treatment of postmenopausal women with hormone-sensitive early breast cancer

Aromatase inhibitors (AIs) have been shown to reduce the risk of breast cancer recurrence and are widely used today as adjuvant therapy in women with early stage endocrine-responsive breast cancer. Aromatase inhibitors may be prescribed as initial hormonal therapy, sequentially following 2–3 years of tamoxifen, or as extended adjuvant therapy (following 5 years of tamoxifen). Aromatase inhibitors are generally well tolerated; however, certain side effects, particularly arthralgia/musculoskeletal symptoms and gynecologic effects, may result in poor adherence to treatment. Patients receiving adjuvant therapy with an AI should be counseled regarding possible side effects and the importance of completing treatment. Interventions to ameliorate side effects should be individualized based on symptoms, comorbid conditions, and pre-existing therapies. In addition, bone and cardiovascular health should be monitored during AI therapy. Prompt therapeutic management of common side effects associated with AIs may provide patients with the opportunity to receive the full benefit of their adjuvant hormonal treatment while minimizing toxicity.     

Exploring novel targets of basal-like breast carcinoma by comparative gene profiling and mechanism analysis

Current adjuvant treatment modalities for breast cancer that express the estrogen receptor or progesterone receptor include adjuvant anti-estrogen therapies, and tamoxifen and aromatase inhibitors. Bone, including the jaw, is an endocrine-sensitive organ, as are other oral structures. This review examines the potential links between adjuvant anti-estrogen treatments in postmenopausal women with hormone receptor positive breast cancer and oral health. A search of PubMed, EMBASE, CENTRAL, and the Web of Knowledge was conducted using combinations of key terms “breast,” “cancer,” “neoplasm,” “Tamoxifen,” “Aromatase Inhibitor,” “chemotherapy,” “hormone therapy,” “alveolar bone loss,” “postmenopausal bone loss,” “estrogen,” “SERM,” “hormone replacement therapy,” and “quality of life.” We selected articles published in peer-reviewed journals in the English. The authors found no studies reporting on periodontal diseases, alveolar bone loss, oral health, or oral health-related quality of life in association with anti-estrogen breast cancer treatments in postmenopausal women. Periodontal diseases, alveolar bone density, tooth loss, and conditions of the soft tissues of the mouth have all been associated with menopausal status supporting the hypothesis that the soft tissues and bone of the oral cavity could be negatively affected by anti-estrogen therapy. As a conclusion, the impact of adjuvant endocrine breast cancer therapy on the oral health of postmenopausal women is undefined. The structures of the oral cavity are influenced by estrogen; therefore, anti-estrogen therapies may carry the risk of oral toxicities. Oral health care for breast cancer patients is an important but understudied aspect of cancer survivorship.     

Aromatase inhibitors as adjuvant therapy for postmenopausal patients with early stage breast cancer

Endocrine therapy of hormone receptor-positive breast tumors is widely used as palliative therapy for metastatic breast cancer and as adjuvant therapy for early stage breast cancer. Tamoxifen has been the definitive standard of hormonal therapies for the last 30 years because of its documented efficacy and reasonable safety profile. Based on encouraging results from trials utilizing the selective, third generation aromatase inhibitors (AIs) in metastatic breast cancer, a number of trials were designed to examine these agents as adjuvant therapies. Trials directly comparing AIs with tamoxifen have, to date, demonstrated superior disease-free-survival with AIs. Likewise, trials examining the use of AIs after tamoxifen have demonstrated better outcomes compared with tamoxifen alone. Additionally, letrozole has been demonstrated to result in superior disease-free-survival after 5 years of adjuvant tamoxifen, compared with no further therapy. In general, the AIs are tolerated at least as well as tamoxifen but decrease bone mineral density and increase osteoporosis due to their lack of estrogenic effects on bone. Based on the fact that AIs appear more effective at preventing contralateral breast cancers than tamoxifen, they are being examined as breast cancer preventives. Despite available data using the AIs as adjuvant therapies, many questions remain unanswered, and further trials will be needed to address these important issues.     

The causes and treatment of bone loss associated with carcinoma of the breast

Despite an increasing incidence, the outlook for women with early breast cancer has improved considerably over recent years with a steady fall in the death rate in most western countries. This is due, at least in part, to the widespread use of adjuvant systemic therapy. However, some of these treatments have adverse effects on bone metabolism with increased bone loss which may result in osteoporosis and associated fractures. Most of the effects on bone are mediated by endocrine changes, either induction of an early menopause by chemotherapy and ovarian ablation, or further suppression of postmenopausal circulating oestrogens by aromatase inhibitors. There may also be direct effects of chemotherapy on bone cell function. The pathophysiology of osteoporosis in breast cancer patients, the methods of assessment and treatment options are reviewed. Bone health is a highly topical issue in breast cancer with the emergence of data supporting the use of several years of treatment with aromatase inhibitors. Guidelines on who and how to screen for bone loss, and simple, safe strategies for treatment to prevent osteoporosis are presented.     

Adjuvant bisphosphonates in endocrine-responsive breast cancer: what is their place in therapy?

Recent advances in the treatment of early breast cancer have improved clinical outcomes and prolonged survival, especially in women with endocrine-responsive disease. However, cancer therapies including cytotoxic chemotherapy, ovarian suppression, and aromatase inhibitors can drastically reduce circulating estrogen, increasing bone loss and fracture risk. Because most women with early breast cancer will live for many years, it is important to protect bone health during cancer therapy. Several recent clinical trials combining adjuvant endocrine therapy with bisphosphonates have demonstrated efficacy for preventing cancer treatment-induced bone loss in pre- and postmenopausal women with early breast cancer. The largest body of evidence supporting the use of adjuvant bisphosphonates comes from studies with zoledronic acid; however, studies with risedronate, ibandronate, and denosumab (a biologic agent) have also demonstrated efficacy for preventing bone loss. Adding zoledronic acid to endocrine therapy prevents bone loss and improves bone mineral density (BMD). In addition, preclinical studies suggest that bisphosphonates have direct and indirect antitumor activity, such as inducing tumor cell apoptosis, reducing tumor cell adhesion and invasion, reducing angiogenesis, activating immune responses, and synergy with chemotherapy agents, among others. Clinical trials have demonstrated significantly improved disease-free survival in patients receiving adjuvant endocrine therapy plus zoledronic acid compared with endocrine therapy alone. Ongoing studies will further define the role of adjuvant bisphosphonates in maintaining bone health and improving clinical outcomes. The available evidence suggests that pre- and postmenopausal patients may receive clinical benefit from including bisphosphonates as part of their adjuvant treatment regimen for endocrine-responsive early breast cancer.     

Tamoxifen and aromatase inhibitors in the treatment of breast cancer in menopausal women: pharmacological and clinical aspects

Estrogen is the main hormone involved in the development and growth of hormone-dependent breast cancer. Endocrine adjuvant treatment in recent years focused primarily on the use of SERMs, mainly tamoxifen. Tamoxifen actions are complex. It acts by competitive antagonism of estrogen at its receptor site. It has beneficial agonistic effects in preventing bone demineralization in postmenopausal women, but a detrimental agonistic effect by increasing the risk of uterine cancer and of thrombo-embolism. However, the situation is changing rapidly with the introduction of recent aromatase inhibitors, which display high specificity towards aromatase. They suppress plasma estrogen levels in postmenopausal women by inhibiting or inactivating aromatase, the enzyme responsible of the synthesis of estrogens from androgenic substrates. A complete estrogen deprivation in target tissues may eventually induce osteoporosis. Unlike tamoxifen, aromatase inhibitors have no partial agonistic action. During the last 20 years, adjuvant tamoxifen treatment for 5 years was the "gold standard" endocrine treatment in postmenopausal women with hormone-receptor-positive breast cancers. A 25% reduction risk of deaths was observed. Recently, the results of clinical trials comparing aromatase inhibitors to tamoxifen in post menopausal women with hormone-dependent breast cancer showed a benefit in favor of aromatase inhibitors in reducing the risk of recurrence. These trials were either comparative (for anastrozole) or sequential (for anastrozole, letrozole and exemestane). The issues of long term adverse effects (bone) and hormone treatment sequence remain to be addressed.