Effects of adjuvant aromatase inhibitor therapy on lipid profiles

How aromatase inhibitors affect lipids is of great interest. Compared with tamoxifen, adjuvant anastrozole and letrozole are associated with increased incidences of hypercholesterolemia, while similar data are lacking for exemestane in the adjuvant setting. No significant differences in lipid profiles occurred with extended adjuvant exemestane compared with placebo, but total cholesterol and low-density lipoprotein levels increased significantly above baseline in both groups over 6 months. Likewise, no significant differences in hypercholesterolemia rates occurred between extended adjuvant letrozole and placebo. A lipid substudy further confirmed that letrozole did not significantly alter serum lipids for 36 months compared with placebo. Thus, although aromatase inhibitors lack the lipid-lowering properties of tamoxifen, no significant worsening of lipid levels occurs with their use. Patients would benefit from lifestyle changes and routine monitoring of serum lipids. Breast cancer therapy trials often report serum lipid parameters, but assessing the quality and overall significance of the data can be difficult. Methodology of data collection varies among trials and the concomitant use of lipid-modifying medication is often not reported. This review discusses the current understanding of the influence of lipid levels on cardiovascular risk in women and presents key findings on the effects of adjuvant aromatase inhibitor therapy on lipid profiles.     

Towards optimal endocrine therapy for hormone-sensitive breast cancer: initial versus sequential adjuvant aromatase inhibition

Patients with hormone-receptor-positive early breast cancer have a significant risk of recurrence despite the use of adjuvant tamoxifen. The third-generation aromatase inhibitors letrozole, anastrozole, and exemestane offer promise as alternative or additional therapy to tamoxifen. As extended adjuvant therapy following completion of 5 years of tamoxifen, letrozole further decreased the risk of recurrence compared with placebo. Compared with tamoxifen, both letrozole and anastrozole significantly reduced the risk of recurrence when used as initial adjuvant therapy, and in the short term both were better tolerated than tamoxifen. Anastrozole and exemestane both reduced the risk of relapse when started after 2-3 years of tamoxifen compared with continued tamoxifen treatment; the results of letrozole in this setting are expected in 2008. These data establish adjuvant aromatase inhibitors as effective alternatives to tamoxifen. Only limited data are currently available to inform the choice between an aromatase inhibitor as either initial adjuvant therapy or sequentially after tamoxifen. Future results from the Breast International Group (BIG) 1-98 trial will further clarify strategies for the adjuvant use of aromatase inhibitors. Here, we critically review the evidence for adjuvant use of aromatase inhibitors. Comparison is made between initial aromatase inhibition, switching, and extended adjuvant strategies. Practical recommendations are given for the endocrine treatment of post-menopausal breast cancer.     

Safety of adjuvant aromatase inhibitor therapy

The long-term effects of aromatase inhibitors (AIs) on lipids and bone and cardiovascular and gynecological health are of particular interest to clinicians. The safety data of anastrozole, letrozole, and exemestane are limited to trials with follow-up periods of 5 years or less, and much of the data arise from comparisons with tamoxifen, a drug that has both estrogen agonist and antagonist effects. With the lack of extensive long-term data, indirect comparisons between the safety profiles of the AIs provide some insights. Although results from these indirect comparisons should be interpreted cautiously, they may assist physicians in the decision-making process. Thus far, AIs confer an increased risk of bone loss and osteoporosis and fractures, while the effects on lipid profiles and cardiovascular health seem to indicate only that AIs lack the cardioprotective and lipid-lowering effects of tamoxifen. Some data also are available from comparisons with placebo, a more appropriate comparator to investigate the tolerability and safety of a specific drug. In the MA.17 trial, patients receiving letrozole experienced similar rates of cardiovascular ischemic events and hypercholesterolemia compared with those on placebo. The significant clinical benefits of AIs compared with tamoxifen have been achieved without worsening quality of life.     

The role of aromatase inhibitors as adjuvant therapy for early breast cancer in postmenopausal women

For endocrine therapy of hormone-sensitive advanced breast cancer in postmenopausal women, the third-generation aromatase inhibitors, letrozole, anastrozole, and exemestane, are effective both as alternatives to tamoxifen in first-line treatment and following first-line tamoxifen failure. These three agents are currently being evaluated as adjuvant therapy of early breast cancer, again relative to the standard, tamoxifen. Three treatment strategies are under investigation: replacement of tamoxifen as adjuvant therapy for 5 years (early adjuvant therapy); sequencing of tamoxifen before or after an aromatase inhibitor during the first 5 years (early sequential adjuvant therapy); or following 5 years of tamoxifen (extended adjuvant therapy). Results of the first early adjuvant trial (Arimidex, Tamoxifen Alone or in Combination [ATAC]) demonstrated that anastrozole was significantly more effective than tamoxifen in reducing the risk of disease recurrence. Two trials sequencing 2-3 years of an aromatase inhibitor after 2-3 years of tamoxifen have also reported results. A large trial (International Collaborative Cancer Group [ICCG] trial 96) found switching to exemestane to be significantly superior to continuing on tamoxifen in disease-free survival, and in a small study (Italian Tamoxifen Arimidex [ITA] trial), similarly sequencing anastrozole after tamoxifen significantly reduced the hazard of recurrence compared with remaining on tamoxifen. Extended adjuvant therapy with 5 years of letrozole versus placebo following 5 years of tamoxifen was evaluated in the MA.17 trial. Compared with placebo, letrozole resulted in a significant improvement in disease-free survival that was irrespective of whether patients had lymph node-positive or -negative tumours. Results of these four trials emphasise the important role of aromatase inhibitors in the adjuvant setting, yet the optimal approach still needs to be defined. A number of trials further evaluating the three adjuvant treatment strategies are ongoing.     

Aromatase inhibitors in adjuvant therapy for hormone receptor positive breast cancer: a systematic review

BACKGROUND: A systematic review was undertaken to review the evidence for the use of third-generation aromatase inhibitors (anastrozole, letrozole and exemestane) as adjuvant therapy for post-menopausal women with early-stage, hormone receptor-positive breast cancer and to develop and support recommendations for their use, with regard to three areas: aromatase inhibitors compared to tamoxifen, aromatase inhibitors in sequence with tamoxifen for a total of five years, and aromatase inhibitors given after five years of tamoxifen therapy. METHODS: MEDLINE, EMBASE, American Society of Clinical Oncology and San Antonio Breast Cancer Symposium proceedings, and the Cochrane Library were searched to May 2007 for reports of randomized controlled trials that met the inclusion criteria. RESULTS: Nine randomized controlled trials and one meta-analysis of three of these trials were identified that reported efficacy data. Eight of these trials reported significantly improved disease-free survival in the arms that involved aromatase inhibitors. The meta-analysis reported significantly improved overall survival among all patients, as did one individual trial. One trial of five years letrozole or placebo after five years tamoxifen found improved overall survival among node-positive patients. CONCLUSIONS: Aromatase inhibitors provide an alternative to tamoxifen as adjuvant therapy for post-menopausal, hormone-receptor-positive breast cancer patients. The options include anastrozole and letrozole for five years, as well as anastrozole and exemestane following two to three years of tamoxifen, for a total five years of hormonal therapy. Five years of letrozole should be considered following five years of tamoxifen. Patients receiving aromatase inhibitors should be monitored for changes in bone mineral density and for cardiovascular disease risk factors and outcomes.     

Optimal adjuvant hormonal therapy in postmenopausal women with hormone-receptor-positive early breast cancer: have we answered the question?

Adjuvant endocrine therapy is the most important systemic treatment for postmenopausal women with hormone-receptor-positive early breast cancer following surgery. Most trials have shown that the third-generation aromatase inhibitors, anastrozole, letrozole (LET), and exemestane, significantly prolong disease-free survival compared with tamoxifen. However, an overall survival benefit with aromatase inhibitors was observed in only three trials to date, in retrospective analyses from selected groups of patients: sequential analysis in the Austrian Breast & Colorectal Study Group 8, switch analysis in the Intergroup Exemestane Study, and analysis of initial letrozole in Breast International Group 1–98 study. Although the priming effect observed in preclinical models and breast cancer patients provides a rationale for sequencing adjuvant endocrine treatment with tamoxifen and aromatase inhibitors, the optimal strategy for adjuvant endocrine treatment has yet to be determined. This review discusses aromatase inhibitor monotherapy, sequential adjuvant treatment with tamoxifen followed by an aromatase inhibitor, and sequential adjuvant treatment with an aromatase inhibitor followed by tamoxifen. Available data in support of and against each strategy is evaluated. The safety profiles of tamoxifen and aromatase inhibitors is also examined.     

The breast cancer continuum in hormone-receptor-positive breast cancer in postmenopausal women: evolving management options focusing on aromatase inhibitors.

There are now a number of highly effective options for the treatment of hormone-receptor-positive breast cancer. Although tamoxifen was the standard hormonal treatment for many years, we now have another option for postmenopausal women: the third-generation aromatase inhibitors (AIs) anastrozole, exemestane and letrozole. A number of trials have investigated the use of third-generation AIs compared with tamoxifen throughout the continuum of treatment settings for postmenopausal women with breast cancer. In the neoadjuvant setting, letrozole, given for 4 months, resulted in better overall clinical response and breast-conserving surgery rates than tamoxifen. The Immediate Preoperative Anastrozole Tamoxifen or Combined with Tamoxifen trial gave anastrozole for 3 months with no difference in clinical response but significantly improved breast-conserving surgery rates. Compared with tamoxifen, anastrozole and letrozole significantly improved disease-free survival as early adjuvant treatment for hormone-receptor-positive disease. Switching to anastrozole or exemestane after 2 to 3 years of adjuvant tamoxifen for a total of 5 years of therapy was also more effective than continued tamoxifen. All three agents are approved in the early adjuvant or switching setting in the USA. Letrozole following 5 years of tamoxifen as extended adjuvant treatment improved disease-free survival and, in the node-positive subgroup, overall survival when compared with placebo. Anastrozole and letrozole are both approved for the first-line treatment of hormone-sensitive advanced breast cancer in postmenopausal women; letrozole showed an improved response rate compared with tamoxifen. Anastrozole, letrozole and exemestane are all indicated for the second-line treatment of advanced breast cancer. In summary, third-generation AIs have been shown to have superior efficacy over tamoxifen in the metastatic, neoadjuvant and adjuvant settings and to improve outcome as extended adjuvant therapy following 5 years of tamoxifen. Ongoing studies will further define the role of sequential adjuvant treatment. Appropriate duration of treatment is another important area of investigation. This review will cover hormonal therapy for postmenopausal women with breast cancer and will not address the treatment of premenopausal women.     

An overview of the pharmacology and pharmacokinetics of the newer generation aromatase inhibitors anastrozole,letrozole, and exemestane

BACKGROUND: The newer generation, nonsteroidal aromatase inhibitors (AIs) anastrozole and letrozole have shown superior efficacy compared with tamoxifen as first-line treatments and compared with megestrol acetate as second-line therapy in postmenopausal women with advanced breast carcinoma. In an open-label, Phase II trial, it was reported that exemestane showed numerical superiority compared with tamoxifen for objective response and clinical benefit. Because these agents ultimately may be administered for periods of up to 5 years in the adjuvant setting, it is of increasing importance to assess their tolerability and pharmacologic profiles. METHODS: In the absence of data from direct clinical comparisons, the published literature was reviewed for the clinical pharmacology, pharmacokinetic characteristics, and selectivity profiles of anastrozole, letrozole, and exemestane. RESULTS: At clinically administered doses, the plasma half-lives of anastrozole (1 mg once daily), letrozole (2.5 mg once daily), and exemestane (25 mg once daily) were 41-48 hours, 2-4 days, and 27 hours, respectively. The time to steady-state plasma levels was 7 days for both anastrozole and exemestane and 60 days for letrozole. Androgenic side effects have been reported only with exemestane. Anastrozole treatment had no impact on plasma lipid levels, whereas both letrozole and exemestane had an unfavorable effect on plasma lipid levels. In indirect comparisons, anastrozole showed the highest degree of selectivity compared with letrozole and exemestane in terms of a lack of effect on adrenosteroidogenesis. CONCLUSIONS: All three AIs demonstrated clinical efficacy over preexisting treatments. However, there were differences in terms of pharmacokinetics and effects on lipid levels and adrenosteroidogenesis. The long-term clinical significance of these differences remains to be elucidated.     

Adjuvant aromatase inhibitor therapy for early breast cancer: A review of the most recent data

Tamoxifen is the established adjuvant treatment for postmenopausal women with hormone-sensitive early breast cancer. However, the side-effects associated with tamoxifen therapy have prompted a search for safer and potentially more effective endocrine agents. Results from randomized trials of the third-generation aromatase inhibitors, anastrozole, letrozole and exemestane, demonstrating improved efficacy compared with tamoxifen and favorable tolerability profiles, are discussed in this review.     

The potency and clinical efficacy of aromatase inhibitors across the breast cancer continuum

The strategy of using estrogen suppression to treat breast cancer led to the development of aromatase inhibitors, including the third-generation nonsteroidal compounds anastrozole and letrozole, and the steroidal compound exemestane. Aromatase inhibitors potently inhibit aromatase activity and also suppress estrogen levels in plasma and tissue. In clinical studies in postmenopausal women with breast cancer, third-generation aromatase inhibitors were shown superior to tamoxifen for the treatment of metastatic disease. Studies of adjuvant therapy with aromatase inhibitors include (i) head-to-head studies of 5 years of the aromatase inhibitor versus 5 years of tamoxifen monotherapy; (ii) sequential therapy of 2–3 years of tamoxifen followed by an aromatase inhibitor (or the opposite sequence) versus 5 years of tamoxifen monotherapy; (iii) extended therapy with an aromatase inhibitor after 5 years of tamoxifen; and (iv) sequential therapy with an aromatase inhibitor versus aromatase inhibitor monotherapy. Recent results from the Arimidex, Tamoxifen, Alone or in Combination and Breast International Group 1–98 trials advocate using an aromatase inhibitor upfront. This article examines the clinical data with aromatase inhibitors, following a brief summary of their pharmacology.     

Optimal treatment strategies in hormone-responsive early breast cancer: the role of aromatase inhibitors

Results from large controlled clinical trials have identified the third-generation aromatase inhibitors (AIs) as the first significant therapeutic advance in the adjuvant treatment of hormone receptor-positive (HR+) early breast cancer in postmenopausal women since the introduction of tamoxifen. Although all 3 agents, letrozole, exemestane and anastrozole, provide benefits compared with a 5-year course of tamoxifen, the optimum strategy for adjuvant AI therapy has not yet been defined. AIs have been studied upfront, in sequence with tamoxifen, in therapy switch strategies after 2-3 years of tamoxifen, and after the completion of standard adjuvant tamoxifen. Clearly, only upfront treatment with an AI can address the peak risk of relapse during the first 2-3 years after surgery, and both letrozole and anastrozole significantly reduce relapses compared with tamoxifen in this setting. Switching to exemestane or anastrozole benefits women who are disease-free following 2-3 years of tamoxifen, and women who have successfully completed the standard 5 years of tamoxifen can benefit from extended adjuvant letrozole therapy. Ongoing studies will help to determine the optimum treatment strategy, and answer other important questions, such as whether the AIs differ clinically, what influence HR expression profiles have on outcomes, and what long-term toxicities may be associated with these highly effective agents.     

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.     

Aromatase inhibitors in breast cancer therapy

Recent advances have been made in the hormonal treatment of breast cancer with the advent of third-generation aromatase inhibitors (anastrozole, letrozole, and exemestane). These newer agents have substantial antitumor activity and appear to be as effective as tamoxifen, with fewer adverse effects. Recent reports indicate that anastrozole is more effective than tamoxifen as adjuvant endocrine therapy in postmenopausal women with breast cancer. This report provides an overview of the clinical trials conducted to date with the aromatase inhibitors as first- and second-line therapies, with an emphasis on recently updated analyses comparing anastrozole with tamoxifen in the adjuvant setting.     

Antiaromatase agents: evolving role in adjuvant therapy

The goal of adjuvant hormonal therapy is to prevent breast cancer recurrence. Standard therapy with tamoxifen has shown great value in the adjuvant setting; however, its tolerability profile can render it unsuitable for some patients. The aromatase inactivator, exemestane, and the 2 aromatase inhibitors, letrozole and anastrozole, have been shown to be equivalent or superior to tamoxifen with respect to multiple endpoints in patients with metastatic breast cancer. With tolerability profiles that are similar to, and in many cases, more acceptable than that of tamoxifen, and efficacy potentially superior to tamoxifen, studies using the antiaromatase agents as adjuvant therapy are currently ongoing. These trials will answer some important questions, such as the order in which adjuvant hormonal therapies are selected to maximize efficacy, whether the antiaromatase agents show improved tolerability, and whether combination therapy is more effective than monotherapy.     

The use of third-generation aromatase inhibitors and tamoxifen in the adjuvant treatment of postmenopausal patients with hormone-dependent breast cancer: evidence based review

(1) Worldwide, breast cancer is the most common type of cancer in women, and the second most frequently diagnosed cancer overall.(2) Since its approval approximately 20 years ago, a 5-year course of tamoxifen has been the standard adjuvant therapy for patients with hormone-dependent breast cancer.(3) Recently, data from large randomised clinical trials have indicated that the third-generation aromatase inhibitors (letrozole, anastrozole and exemestane) are more effective than tamoxifen as adjuvant therapy in postmenopausal women with operable breast cancer when given either initially, or sequentially following initial tamoxifen therapy, within the first five years post-operatively.(4) One large randomised trial demonstrated that administration of letrozole to high-risk (node-positive) postmenopausal patients who have completed 5 years' adjuvant tamoxifen further prevents late recurrences and contralateral breast cancer, contrary to the lack of obvious benefit of extending tamoxifen treatment to 10 years found in another large randomised study.(5) Aromatase inhibitors and tamoxifen should not be administered concomitantly as this does not provide additional benefit, and a large, randomised study demonstrated reduced disease-free survival with the combination of anastrozole plus tamoxifen compared with anastrozole alone.(6) Further studies are required to establish whether the third-generation aromatase inhibitors prolong overall survival compared with tamoxifen, to evaluate their long-term efficacy and tolerability profiles, and to determine the optimal treatment duration with these agents.     

The effects of aromatase inhibitors on lipids and thrombosis

Oestrogen is known to influence blood lipid levels and though its cardioprotective effects are less clear than once thought, there remains concern that reduction of oestrogen levels during hormonal treatment for breast cancer may have an adverse effect on cardiovascular risk. While tamoxifen has been shown to improve lipid profiles, the aromatase inhibitors have a very different mode of action and do not possess the oestrogen-agonistic effects of tamoxifen. At present, there are few data on the effects of these agents on lipid profiles. Available data are mixed, but suggest that the different aromatase inhibitors have different effects on lipid profiles. Some studies show anastrozole as generally having little effect on lipids, while others have indicated adverse effects on lipid profiles/increased hypercholesterolaemia. Letrozole has been associated with adverse effects on lipid profiles in some studies, including BIG 1-98, but short-term data from randomised trials do not show increased cardiovascular morbidity. By contrast, exemestane, which has been studied in slightly more detail, may either have little effect or may be associated with slightly improved lipid profiles. In general, the changes have been small and are likely to be of little relevance in women with advanced breast cancer, but if these agents come to be used in early breast cancer, their impact on lipid profiles may become more important. Many studies are currently underway with the aromatase inhibitors, with safety assessments including monitoring lipid levels. The results of these studies are keenly awaited.     

Defining the roles of aromatase inhibitors in the adjuvant treatment of early-stage breast cancer

The widespread use of tamoxifen has led to significant improvements in survival for postmenopausal women with early-stage hormone receptor-positive breast cancer; however, approximately 30% of patients die despite receiving tamoxifen as adjuvant treatment. In addition, concerns exist regarding tamoxifen-associated side effects, including endometrial cancer and thromboembolic disease. The development of the third-generation aromatase inhibitors (AIs; anastrozole, exemestane, and letrozole) therefore represented a welcome potential alternative to tamoxifen. Several clinical trials have demonstrated the superiority of AIs over tamoxifen in the adjuvant treatment of postmenopausal women with hormone-sensitive breast cancer, but these trials differ in their design and in the characteristics of their patient populations. This review discusses the different designs of the primary adjuvant, switching, extended adjuvant, and sequencing trials that are investigating the use of AIs in the adjuvant treatment of breast cancer and provides direction regarding how the data from these trials could be used to guide treatment choice. This review also demonstrates why one should not extrapolate results from clinical trials to clinical situations that differ from the clinical trial or from clinical trials investigating a particular AI to clinical situations involving another AI.     

Lipid changes in breast cancer patients on exemestane treatment: final results of the TEAM Greek substudy

Background: The Greek substudy of the Tamoxifen and ExemestaneAdjuvant Multicenter International trial compared the effectof exemestane on the lipid profile of postmenopausal, breastcancer patients to that of tamoxifen in the adjuvant setting. Patients and methods: Lipidemic profile changes were studiedin 142 postmenopausal patients randomized to receive eitheradjuvant exemestane (n = 77) or tamoxifen (n = 65). Total cholesterol(TC), high-density lipoprotein (HDL), low-density lipoprotein(LDL) and serum triglyceride (TRG) levels were measured at baselineand then every 3 months for the first 12 months of treatmentand at 18 and 24 months. Results: A trend for a reduction in TC was found in both treatmentarms; however, TC and LDL levels were consistently and significantlydecreased in tamoxifen arm only. The mean HDL level was higherfor the tamoxifen arm compared with the exemestane arm acrosstime. No significant trend was detected throughout the studyperiod on TRG levels on either arm. Conclusions: Unlike tamoxifen's beneficial effect on TC andLDL levels, exemestane appears to have a neutral effect on lipidemicprofile of postmenopausal, breast cancer patients. These dataoffer additional information with regard to the safety and tolerabilityof exemestane treatment in the adjuvant setting. Key words: aromatase inhibitors, breast cancer, cholesterol, exemestane, lipids, tamoxifen, TEAM trial Received for publication May 4, 2008. Revision received July 3, 2008. Accepted for publication July 4, 2008.     

Reducing the risk of distant metastases in breast cancer patients: role of aromatase inhibitors

Breast cancer continues to be one of the most prominent causes of cancer death among women worldwide. Mortality in breast cancer is most commonly caused by the occurrence of distant metastases. Thus, treatments that reduce the risk of distant metastases are likely to improve survival. The third-generation aromatase inhibitors (AIs), including anastrozole, letrozole, and exemestane, have been investigated as alternatives to tamoxifen for the adjuvant treatment of early, endocrine-responsive breast cancer. Results from several large trials have established the superior efficacy of the AIs over tamoxifen in reducing the risk of recurrences when used as upfront, switch, and extended adjuvant therapy. Here, we review recent updated results obtained with AIs as adjuvant therapy, in terms of reducing the risk of distant metastases.     

Safety considerations of adjuvant therapy in early breast cancer in postmenopausal women

Because of its proven efficacy profile based on long-term data, tamoxifen has been the standard adjuvant endocrine therapy for hormone-sensitive early breast cancer for the past 30 years. However, there is well-established evidence that long-term use of tamoxifen is associated with serious side effects. As adjuvant endocrine therapy is generally administered for long periods of time, the safety and tolerability of agents used in this setting are of particular importance. Due to their superior efficacy over tamoxifen, newer agents, such as the third-generation aromatase inhibitors (AIs), are already established therapies for the treatment of advanced breast cancer. In addition, recent trials indicate that the AI anastrozole ('Arimidex') has improved efficacy compared with tamoxifen in the adjuvant setting in postmenopausal women. The other third-generation AIs have reported disease-free survival benefits but not in the absence of prior treatment with tamoxifen; letrozole ('Femara') has been compared with placebo following 5 years of tamoxifen therapy and exemestane ('Aromasin') has been compared with tamoxifen following 2-3 years of prior treatment with tamoxifen. Long-term safety data show that anastrozole also has a more favorable overall safety profile compared with tamoxifen, particularly in terms of life-threatening events such as endometrial cancer and thromboembolism. Anastrozole alone, therefore, provides a new option for adjuvant therapy in postmenopausal women with hormone-receptor-positive early breast cancer. The AIs have differing pharmacological profiles, which may translate into dissimilar adverse event profiles in the adjuvant treatment setting, but patient follow-up in most trials is relatively short to make a valid comparison. It cannot, therefore, be assumed that all AIs will be equally well tolerated in the adjuvant setting. Further data on the long-term safety of AIs other than anastrozole are therefore required to allow overall risk:benefit assessments on these agents to be made.