Letrozole: a pharmacoeconomic review of its use in postmenopausal women with breast cancer

Letrozole (Femara), an aromatase inhibitor that blocks estrogen synthesis by inhibiting the final step of the estrogen biosynthetic pathway, is approved for use in a wide range of breast cancer settings. Randomised clinical trials in postmenopausal women with hormone-responsive early-stage breast cancer have demonstrated that, as adjuvant therapy, letrozole has greater efficacy than tamoxifen. It is also more effective than placebo as extended adjuvant therapy after completion of tamoxifen therapy in these patients. In women with hormone-responsive advanced breast cancer, letrozole is superior to tamoxifen in prolonging the time to disease progression and time to treatment failure in a first-line setting, and is at least as effective as anastrozole and more effective than megestrol for some endpoints (in one of two trials) in a second-line setting. Letrozole is generally well tolerated, and in a health-related quality-of-life analysis from a large clinical trial, patient well-being with letrozole as extended adjuvant therapy did not differ from that with placebo. Modelled analyses from the UK and the US suggest that, in postmenopausal women with hormone-receptor-positive early-stage breast cancer, letrozole is likely to be a cost-effective alternative to tamoxifen as adjuvant therapy; moreover, using letrozole as extended adjuvant therapy after tamoxifen, rather than no further treatment, is also a cost-effective treatment strategy. Sensitivity analyses have shown these results to be robust. In terms of direct healthcare costs, pharmacoeconomic models suggest that letrozole is a cost-effective alternative to tamoxifen as first-line therapy in postmenopausal women with hormone-responsive advanced breast cancer from the perspectives of the UK NHS, the Canadian and Italian public healthcare systems and the Japanese national health insurance system. Incremental costs per QALY or progression-free year gained over tamoxifen were well within the recommended limits for acceptability of new agents that are more effective and more expensive than existing therapies in the UK, Japan and Canada. Modelled analyses from the UK and Canada have also suggested that letrozole is cost effective as second-line therapy for advanced breast cancer in postmenopausal women who have disease progression following anti-estrogen therapy. In conclusion, letrozole is an effective and well tolerated treatment for postmenopausal women with early-stage or advanced hormone-responsive breast cancer. Pharmacoeconomic analyses from UK and North American perspectives support the use of letrozole in hormone-responsive early-stage breast cancer in both the adjuvant and extended adjuvant settings. In addition, other modelled analyses conducted in a variety of healthcare systems across different countries consistently suggest that letrozole is cost effective in advanced treatment settings.     

Letrozole: a review of its use in postmenopausal women with breast cancer

Letrozole (Femara), a nonsteroidal, third-generation aromatase inhibitor administered orally once daily, has shown efficacy in the treatment of postmenopausal women with early-stage or advanced, hormone-sensitive breast cancer. In early-stage disease, extending adjuvant endocrine therapy with letrozole (beyond the standard 5-year period of tamoxifen) improved disease-free survival; compared with placebo there was a 43% relative reduction in disease recurrences or new contralateral breast tumours at a median follow-up of 2.4 years. The results of 4 months' neoadjuvant treatment with letrozole or tamoxifen in postmenopausal women with untreated primary disease favour letrozole. In advanced breast cancer, letrozole was superior to tamoxifen as first-line treatment; time to disease progression was significantly longer (9.4 vs 6.0 months, p < 0.0001) and objective response rate was significantly greater with letrozole, but median overall survival was similar between groups. For second-line therapy of advanced breast cancer that had progressed on antiestrogen therapy, letrozole showed efficacy equivalent to that of anastrozole and similar to or better than that of megestrol acetate. Letrozole is generally well tolerated and has a similar tolerability profile to tamoxifen; the most common treatment-related adverse events were hot flushes, nausea and hair thinning. In patients with tumours that had progressed on antiestrogen therapy, letrozole was tolerated as least as well as, or better than, anastrozole or megestrol acetate. In the trial of extended adjuvant therapy, adverse events reported more frequently with letrozole than placebo were hot flushes, arthralgia, myalgia and arthritis. The long-term effects of letrozole on bone mineral density or lipid profile have not been determined and these parameters may require monitoring. In several pharmacoeconomic modelling studies from various public healthcare system perspectives, letrozole was considered a cost effective choice for first-line (vs tamoxifen) or second-line (vs megestrol acetate) treatment for advanced breast cancer in postmenopausal women. In conclusion, letrozole 2.5 mg/day is effective in the treatment of postmenopausal women with early-stage or advanced breast cancer. The efficacy, cost effectiveness and favourable tolerability profile of letrozole are reflected in current treatment guidelines recommending the drug as first-line therapy for advanced breast cancer. Letrozole is superior to tamoxifen for first-line treatment and is at least as effective as standard second-line treatments in disease that has progressed on antiestrogen therapy. For early-stage disease, letrozole is superior to tamoxifen in the neoadjuvant setting, and prolongs disease-free survival when administered after the standard 5-year period of adjuvant tamoxifen therapy.     

Letrozole in the treatment of breast cancer

Endocrine therapy, predominantly using the antioestrogen tamoxifen, has long been a key treatment strategy for oestrogen receptor-positive breast cancer. An alternative approach is to treat patients with aromatase inhibitors, which suppress oestrogen biosynthesis. Letrozole, and other third-generation aromatase inhibitors, are highly specific and potent inhibitors of oestrogen production, which markedly reduce circulating oestrogen levels and whole-body aromatisation of androgen precursors after menopause. In postmenopausal women with hormone receptor-positive or receptor-unknown breast cancer, letrozole has been shown to be superior to megestrol acetate and aminoglutethimide in second-line treatment for advanced breast cancer. Letrozole was also superior to tamoxifen in first-line treatment for advanced breast cancer, as well as in systemic preoperative (neoadjuvant) treatment of locally advanced breast cancer. A recent adjuvant trial demonstrated significant superiority of letrozole over tamoxifen in disease-free survival, and another trial demonstrated that treatment for early breast cancer with letrozole, following 5 years of adjuvant tamoxifen (extended adjuvant therapy), significantly improved disease-free survival compared with placebo, irrespective of nodal status. Ongoing trials will determine whether the optimal use of letrozole in the adjuvant therapy of early breast cancer is as a replacement for tamoxifen, or sequenced additionally before or after tamoxifen.     

Letrozole in the treatment of breast cancer

Endocrine therapy, predominantly using the antioestrogen tamoxifen, has long been a key treatment strategy for oestrogen receptor-positive breast cancer. An alternative approach is to treat patients with aromatase inhibitors, which suppress oestrogen biosynthesis. Letrozole, and other third-generation aromatase inhibitors, are highly specific and potent inhibitors of oestrogen production, which markedly reduce circulating oestrogen levels and whole-body aromatisation of androgen precursors after menopause. In postmenopausal women with hormone receptor-positive or receptor-unknown breast cancer, letrozole has been shown to be superior to megestrol acetate and aminoglutethimide in second-line treatment for advanced breast cancer. Letrozole was also superior to tamoxifen in first-line treatment for advanced breast cancer, as well as in systemic preoperative (neoadjuvant) treatment of locally advanced breast cancer. A recent adjuvant trial demonstrated significant superiority of letrozole over tamoxifen in disease-free survival, and another trial demonstrated that treatment for early breast cancer with letrozole, following 5 years of adjuvant tamoxifen (extended adjuvant therapy), significantly improved disease-free survival compared with placebo, irrespective of nodal status. Ongoing trials will determine whether the optimal use of letrozole in the adjuvant therapy of early breast cancer is as a replacement for tamoxifen, or sequenced additionally before or after tamoxifen.     

The role of letrozole (Femara(R)) in breast cancer therapy: A clinical review

Letrozole is a third-generation aromatase inhibitor for use in postmenopausal women with hormonal-sensitive breast cancer. This drug was found to reduce or effectively shrink tumors in a significant number of such patients. It exhibits antitumor activity at a relatively low daily dose, and is highly potent and selective and well tolerated. Results from recent phase III clinical studies have confirmed the efficacy and the key role of this drug in the therapy of advanced breast cancer in postmenopausal women. Moreover, letrozole demonstrated higher activity and lower toxicity compared to tamoxifen in the first-line therapy of postmenopausal women affected with advanced breast cancer. However, it also represents a valid option in second-line therapy after tamoxifen failure. New data on this agent in adjuvant or neoadjuvant treatment also suggest efficacy in the treatment of early breast cancer. This article reviews the clinical data on letrozole in all settings and its future potential in chemoprevention. (c) 2001 Prous Science. All rights reserved.     

Anastrozole

Recent trials have indicated that the aromatase inhibitors (anastrozole, letrozole, exemestane) are more effective than tamoxifen, the standard adjuvant treatment for estrogen receptor-positive breast cancer, both in adjuvant and first-line advanced settings. This paper reviews the mode of action and the main clinical trials done with anastrozole, the only aromatase inhibitor currently licensed for use in the adjuvant setting in estrogen receptor-positive tumors. Results from studies using anastrozole as a first-line treatment in advanced disease strongly suggest that this drug should now be considered as an alternative first-line therapy to tamoxifen in postmenopausal women with estrogen receptor-positive advanced breast cancer. As a second-line treatment in tamoxifen failures, anastrozole has shown a better survival rate and a better side-effect profile than megestrol acetate. Similarly, the use of anastrozole in the adjuvant setting has shown a significantly prolonged disease-free survival time and improved tolerability compared to tamoxifen in postmenopausal breast cancer survivors.     

Adjuvant use of aromatase inhibitors in postmenopausal women with breast cancer.

PURPOSE: Emerging data from clinical trials on the use of aromatase inhibitors in the management of early-stage, hormone-dependent breast cancer in postmenopausal women are reviewed. SUMMARY: Aromatase is the enzyme responsible for the conversion of androgens to estrogens and the only source of estrogens in postmenopausal women. Clinical trials using aromatase inhibitors in the adjuvant treatment of postmenopausal women with breast cancer are few but significant because of their comparative design with tamoxifen given for five years, long regarded as the gold standard for breast cancer treatment. Data from the Anastrozole, Tamoxifen and Combination trial, the MA-17 trial (letrozole compared with placebo), the Italian Tamoxifen Arimidex trial (anastrozole following tamoxifen), and the Intergroup Exemestane Study have shown promising efficacy and safety in the use of these agents. While the optimal aromatase inhibitor for use in the adjuvant setting has not been elucidated, current evidence-based recommendations include using (1) anastrozole as the first adjuvant therapy for five years, (2) tamoxifen for two to three years, then exemestane or anastrozole for the remainder of the five years, and (3) tamoxifen for five years, then letrozole for another five years. CONCLUSION: While their impact on survival has not been determined, aromatase inhibitors are slowly changing the management of early-stage, hormone-dependent breast cancer in postmenopausal women because of improved disease-free survival rates. Their ultimate role in therapy is unknown, but educating patients about the potential risks and benefits will allow them to make informed decisions regarding these data and their breast cancer care.     

Update on the use of letrozole in breast cancer

Endocrine therapy is the mainstay of adjuvant treatment for hormonereceptor-positive early breast cancer. Letrozole is a potent third-generation aromatase inhibitor that suppresses plasma estrogen levels to near-undetectable levels in postmenopausal women. The results of well-controlled clinical trials have demonstrated the efficacy of letrozole over the gold-standard treatment, tamoxifen, in the neoadjuvant and upfront adjuvant settings and over placebo in the extended adjuvant setting (i.e., following 5 years of adjuvant tamoxifen). Important benefits in disease-free survival and especially distant disease-free survival have been demonstrated, in both low- and high-risk subgroups of patients (e.g., node-positive disease, prior chemotherapy). Both the efficacy and safety of letrozole for the adjuvant treatment of breast cancer are reviewed.     

A stochastic economic evaluation of letrozole versus tamoxifen as a first-line hormonal therapy: for advanced breast cancer in postmenopausal patients

BACKGROUND: Letrozole is a third-generation aromatase inhibitor that is a feasible alternative to tamoxifen as a first-line hormonal therapy for patients with advanced breast cancer. OBJECTIVE: This paper presents the results of an economic evaluation comparing letrozole and tamoxifen as first-line hormonal therapies in postmenopausal women diagnosed with advanced breast cancer. PERSPECTIVE: UK National Health Service. DESIGN: A decision model (Markov process) was built describing possible patient pathways from the point of diagnosis to death. The model was populated using patient-specific clinical trial data, data from the existing literature, and expert opinion. Stochastic analyses of the model were undertaken, whereby the majority of the input parameters were described as probability distributions to represent the uncertainty about their true value. Costs were presented in year 2000 values. RESULTS: The baseline results showed that letrozole is a cost-effective alternative to tamoxifen with a mean incremental cost per life-year gained of pound 2342, whilst the incremental cost increases to just over pound 10,000 at the 95th percentile of the cost-effectiveness range (2000 values). CONCLUSIONS: The results of the economic analysis indicate that letrozole is a cost-effective alternative first-line therapy compared with tamoxifen for postmenopausal women with advanced breast cancer, achieving additional life-years with a modest increase in costs.     

Update on the use of aromatase inhibitors in breast cancer

Estrogens are biosynthesised from androgens by the CYP450 enzyme complex called aromatase. Aromatase is expressed in the ovary, placenta, brain, bone, adipose tissue and breast tissue. In breast cancer, intratumoural aromatase is the source for local estrogen production in the tissue. Inhibition of aromatase is an important approach for reducing growth stimulatory effects of estrogens in estrogen-dependent breast cancer. The potent and selective third-generation aromatase inhibitors anastrozole, letrozole and exemestane were introduced to the market as endocrine therapy in postmenopausal patients failing anti-estrogen therapy alone, or multiple hormonal therapies. Anastrozole and letrozole are both non-steroidal aromatase inhibitors that compete with the substrate for binding to the enzyme active site. Exemestane is a mechanism-based steroidal inhibitor that mimics the substrate, is converted by the enzyme to a reactive intermediate, and results in inactivation of aromatase. These third-generation aromatase inhibitors are currently approved as first-line therapy for the treatment of postmenopausal women with metastatic estrogen-dependent breast cancer. The use of an aromatase inhibitor as initial therapy, or after treatment with tamoxifen, is now recommended as adjuvant hormonal therapy for postmenopausal women with hormone-dependent breast cancer. Several clinical studies of aromatase inhibitors focus on the use of these agents in the adjuvant setting, for the treatment of early breast cancer. Recently published results show improved responses with these agents compared with tamoxifen.     

Anastrozole: a review of its use in postmenopausal women with early-stage breast cancer

Anastrozole (Arimidex) is an aromatase inhibitor approved in the EU, the US and in other countries worldwide for use as an adjuvant treatment in postmenopausal women with early-stage, hormone receptor-positive breast cancer. It is also approved in the EU and other countries worldwide for continuing adjuvant treatment in women who have already had 2-3 years of adjuvant tamoxifen treatment for breast cancer.Anastrozole is an effective primary adjuvant treatment for postmenopausal women with early-stage breast cancer. In patients with hormone receptor-positive tumours, 5 years of anastrozole treatment was more efficacious in reducing breast cancer recurrence than 5 years of tamoxifen, both in a head-to-head comparison and in switching trials when given after 2-3 years of tamoxifen treatment. The treatment benefits have now been shown to extend to 100 months following breast surgery. To date, overall survival was better in anastrozole than tamoxifen recipients in one switching trial and in a meta-analysis of three switching trials. There was no increased benefit in health-related quality of life with anastrozole over tamoxifen. In women who had received 5 years of tamoxifen treatment, continuation of treatment with anastrozole further reduced the risk of breast cancer recurrence. Ongoing head-to-head trials against other third-generation aromatase inhibitors will provide data as to its relative efficacy against these agents. Anastrozole is a generally well tolerated treatment for early-stage breast cancer. Like other aromatase inhibitors, its most important adverse effect was an increased risk of bone fractures, which for anastrozole was restricted to the treatment period. It is still unclear whether primary adjuvant treatment extended beyond 5 years is of benefit and whether primary adjuvant treatment with anastrozole for 5 years is preferable to switching to anastrozole after 2-3 years of tamoxifen treatment. However, the evidence to date establishes anastrozole as a valuable adjuvant and extended adjuvant treatment for postmenopausal women with hormone receptor-positive, early-stage breast cancer.     

Aromatase inhibitors

The new non-steroidal and steroidal aromatase inhibitors are at least as effective as megestrol acetate (MA) as second-line hormonal agents in postmenopausal women with breast cancer. However, they are superior to MA in terms of tolerability and adverse effects. Letrozole and exemestane have been shown to be superior to MA in terms of efficacy. Furthermore, exemestane and anastrozole demonstrated a survival advantage over MA. These drugs are therefore considered established second-line hormonal agents. There is a growing body of evidence supporting the role of third-generation aromatase inhibitors as first-line therapy for ER-and/or PgR-positive advanced breast cancer in postmenopausal women, and as a neoadjuvant therapy in postmenopausal women with hormone receptor positive tumours unsuitable for breast conserving surgery. Studies comparing these drugs head-to-head and with adjuvant tamoxifen are currently in progress. The potential role of these drugs in breast cancer prevention is worth investigating.     

Should aromatase inhibitors replace tamoxifen?

Six years ago, we reviewed the selective aromatase inhibitors, anastrozole and letrozole, for the treatment of women with breast cancer. We concluded that anastrozole was at least as effective as megestrol (the standard treatment at that time for women with advanced postmenopausal breast cancer in whom tamoxifen had failed), but that there was insufficient published evidence to decide the place of letrozole in therapy. Since then, these drugs have become standard second-line treatment options for postmenopausal women with locally advanced or metastatic, hormone-receptor-positive breast cancer, and a third selective aromatase inhibitor, [symbol: see text] exemestane (pronounced eks-ee-mes-tane), has been added to the market. Here we consider whether the aromatase inhibitors should replace tamoxifen as first-line therapy.     

Aromatase Inhibitors

Summary

The new non-steroidal and steroidal aromatase inhibitors are at least as effective as megestrol acetate (MA) as second-line hormonal agents in postmenopausal women with breast cancer. However, they are superior to MA in terms of tolerability and adverse effects. Letrozole and exemestane have been shown to be superior to MA in terms of efficacy. Furthermore, exemestane and anastrozole demonstrated a survival advantage over MA. These drugs are therefore considered established second-line hormonal agents. There is a growing body of evidence supporting the role of third-generation aromatase inhibitors as first-line therapy for ER-and/or PgR-positive advanced breast cancer in postmenopausal women, and as a neoadjuvant therapy in postmenopausal women with hormone receptor positive tumours unsuitable for breast conserving surgery. Studies comparing these drugs head-to-head and with adjuvant tamoxifen are currently in progress. The potential role of these drugs in breast cancer prevention is worth investigating.     

Focus on anastrozole and breast cancer

This commentary article provides an overview of recent clinical research trials involving anastrozole and its evolving role in the management of breast cancer. Anti-aromatase agents inhibit the cytochrome P-450 component of the aromatase enzyme complex responsible for the final step of estrogen biosynthesis in peripheral tissues which are the main source of estrogen in postmenopausal women. Anastrozole is a third-generation non-steroidal aromatase inhibitor. It has been shown to be superior to megestrol acetate, in terms of survival and adverse effects, as a second-line therapy in postmenopausal women with estrogen receptor (ER)- and/or progesterone receptor (PgR)-positive advanced breast cancer. Phase III clinical trials have also demonstrated that anastrozole significantly prolongs the time to tumour progression compared with tamoxifen as a first-line therapy for ER- and/or PgR-positive advanced breast cancer in postmenopausal women. Furthermore, the preliminary results of the Arimidex, Tamoxifen, Alone and in Combination (ATAC) study have shown that adjuvant anastrozole is superior to tamoxifen in terms of disease-free survival (DFS), non-musculoskeletal adverse effects and prevention of contralateral breast cancer in postmenopausal women with early, ER-positive breast cancer. Although longer follow-up is required to assess the long-term effects of anastrozole on bone mineral density, cognitive function and overall survival, the drug has been recently approved for adjuvant use in postmenopausal women with early, ER-positive breast cancer who are unable to tolerate tamoxifen or at an increased risk of developing thromboembolism or endometrial cancer. The potential role of anastrozole in the neoadjuvant setting, the management of DCIS, premenopausal breast cancer and breast cancer prevention is currently being investigated.     

Incidence and management of side effects associated with aromatase inhibitors in the adjuvant treatment of breast cancer in postmenopausal women

OBJECTIVE: Third-generation aromatase inhibitors (AIs) are effective and generally well-tolerated as adjuvant therapy. These AIs are now being introduced for the adjuvant treatment of postmenopausal patients with estrogen-receptor-positive early-stage breast cancer. However, questions remain about their long-term safety. This paper summarizes the adverse events reported in third-generation AI trials and comments on the appropriate management of these drug-induced adverse events in patients. METHODS: Papers relating to anastrozole, exemestane, and letrozole were identified through Medline searches, and proceedings of recent oncology meetings were also reviewed to capture relevant emerging data. RESULTS: The most commonly reported adverse events associated with adjuvant AI therapy include hot flushes and musculoskeletal complaints/arthralgia. The incidence of endometrial cancer and thromboembolic events is significantly lower with an AI than with tamoxifen. However, there is a small but significant increase in the risk of osteoporosis and fractures with AI therapy. A potential negative effect on the cardiovascular system, specifically on lipid metabolism, has not been conclusively demonstrated. No significant differences in overall quality of life were observed in studies comparing AIs with tamoxifen or placebo. CONCLUSION: AIs alone and sequenced after tamoxifen are an appropriate option for adjuvant endocrine therapy for most postmenopausal patients with hormone-responsive breast cancer. The incidence of some side effects such as endometrial cancer, stroke, or pulmonary embolism associated with tamoxifen is decreased. Monitoring and management of bone loss associated with AI treatment are essential and are being addressed in ongoing trials. Further studies with longer follow-up are required to clarify the effects of AIs on lipid metabolism and cardiovascular health.     

Letrozole in the treatment of breast cancer

Over the last 30 years the role of tamoxifen in breast cancer treatment has been progressively expanded by clinical investigation to encompass the entire spectrum of disease from cancer chemoprevention to palliation of advanced disease. The primacy of tamoxifen for these indications in postmenopausal women is now under challenge by the selective aromatase inhibitors, a class of endocrine agent that induces oestrogen deprivation rather than oestrogen receptor blockade. This review considers the biochemical, pharmacological and clinical properties of the nonsteroidal aromatase inhibitor letrozole. This agent is superior to tamoxifen for the treatment of metastatic breast cancer, a finding that suggests that letrozole may ultimately eclipse tamoxifen for other indications, including chemoprevention. Further clinical investigation will be necessary to establish the risks and benefits of letrozole versus tamoxifen for each new indication, with adjuvant therapy being the next in line. The object of this review is to provide a reference source on the biochemical, pharmacological and clinical properties of letrozole for clinicians to consider both established and future indications.     

Letrozole in the treatment of breast cancer

Over the last 30 years the role of tamoxifen in breast cancer treatment has been progressively expanded by clinical investigation to encompass the entire spectrum of disease from cancer chemoprevention to palliation of advanced disease. The primacy of tamoxifen for these indications in postmenopausal women is now under challenge by the selective aromatase inhibitors, a class of endocrine agent that induces oestrogen deprivation rather than oestrogen receptor blockade. This review considers the biochemical, pharmacological and clinical properties of the nonsteroidal aromatase inhibitor letrozole. This agent is superior to tamoxifen for the treatment of metastatic breast cancer, a finding that suggests that letrozole may ultimately eclipse tamoxifen for other indications, including chemoprevention. Further clinical investigation will be necessary to establish the risks and benefits of letrozole versus tamoxifen for each new indication, with adjuvant therapy being the next in line. The object of this review is to provide a reference source on the biochemical, pharmacological and clinical properties of letrozole for clinicians to consider both established and future indications.     

Cardiovascular safety profiles of aromatase inhibitors : a comparative review.

Third-generation aromatase inhibitors (AIs) are now being used for the adjuvant treatment of postmenopausal women with breast cancer, and are challenging tamoxifen, the previous 'gold standard' of care, in this setting. This review evaluates the potential clinical impact of anastrozole, letrozole and exemestane on the cardiovascular (CV) system of postmenopausal women with breast cancer. Some data for CV safety are available for AIs from the advanced disease setting; however, most derive from patients being treated for early disease. CV data on anastrozole for the treatment of early breast cancer were taken from the ATAC trial, in which anastrozole was compared with tamoxifen in the primary adjuvant setting, and the ABCSG trial 8/ARNO 95 combined analysis, in which switching to 3 years of anastrozole after 2 years of tamoxifen was compared with the standard 5 years of tamoxifen adjuvant therapy. Letrozole has been studied in the primary adjuvant setting and the adjuvant sequencing setting in the BIG 1-98 study, as well as in extended adjuvant endocrine therapy after 5 years of tamoxifen in the MA-17 trial. For exemestane, results were reviewed from the IES trial, in which switching to exemestane following 2-3 years of adjuvant tamoxifen was compared with continued tamoxifen treatment. All these trials clearly confirmed that all three AIs significantly reduce the risk of thromboembolic events compared with tamoxifen. Data on anastrozole versus tamoxifen from the ATAC trial (68 months' follow-up) showed a similar incidence of myocardial infarctions (MIs), CV deaths and overall deaths for both therapies; however, anastrozole appeared to be associated with a lower incidence of cerebrovascular events compared with tamoxifen. In addition, the ABCSG trial 8/ARNO 95 study reported no difference in terms of MIs for patients switching to anastrozole compared with patients continuing tamoxifen treatment. Data from BIG 1-98 (26 months' follow-up) suggested that primary adjuvant treatment with letrozole may be associated with a significantly greater incidence of CV events and a numerical increase of cerebrovascular and cardiac deaths compared with tamoxifen. However, no increase in CV events with letrozole was reported from the MA-17 trial. In the IES, updated data at 55 months' median follow up showed no significant difference in the incidence of MIs and cardiac deaths between patients who switched to exemestane compared with those who continued tamoxifen. In conclusion, a significantly reduced risk of thromboembolic disease was observed for all three AIs compared with tamoxifen. Anastrozole is, at this point, the only AI with a detailed benefit-risk profile from over 5 years' follow-up in the adjuvant setting. Thus far, no apparent CV-safety concerns have emerged. Preliminary data on letrozole and exemestane suggest that longer follow-up is needed for these two AIs before being able to fully assess their respective long-term CV toxicity profile. The present differences in CV-safety profiles suggest that third-generation AIs should not be considered as equivalents in clinical practice.     

Focus on anastrozole and breast cancer

SUMMARY

This commentary article provides an overview of recent clinical research trials involving anastrozole and its evolving role in the management of breast cancer.

Anti-aromatase agents inhibit the cytochrome P-450 component of the aromatase enzyme complex responsible for the final step of estrogen biosynthesis in peripheral tissues which are the main source of estrogen in postmenopausal women. Anastrozole is a third-generation non-steroidal aromatase inhibitor. It has been shown to be superior to megestrol acetate, in terms of survival and adverse effects, as a second-line therapy in postmenopausal women with estrogen receptor (ER)- and/or progesterone receptor (PgR)-positive advanced breast cancer. Phase III clinical trials have also demonstrated that anastrozole significantly prolongs the time to tumour progression compared with tamoxifen as a first-line therapy for ER- and/or PgR-positive advanced breast cancer in postmenopausal women. Furthermore, the preliminary results of the Arimidex, Tamoxifen, Alone and in Combination (ATAC) study have shown that adjuvant anastrozole is superior to tamoxifen in terms of disease-free survival (DFS), non-musculoskeletal adverse effects and prevention of contralateral breast cancer in postmenopausal women with early, ER-positive breast cancer. Although longer follow-up is required to assess the long-term effects of anastrozole on bone mineral density, cognitive function and overall survival, the drug has been recently approved for adjuvant use in postmenopausal women with early, ER-positive breast cancer who are unable to tolerate tamoxifen or at an increased risk of developing thromboembolism or endometrial cancer.

The potential role of anastrozole in the neoadjuvant setting, the management of DCIS, premenopausal breast cancer and breast cancer prevention is currently being investigated.