Third-generation Aromatase Inhibitors Research Articles

Selective Estrogen-Receptor Modulators and Aromatase Inhibitors: Promising New Medical Therapies for Endometriosis?

Endometriosis is an estrogen-dependent disease and estrogen-related pathways are imbalanced in women with endometriosis. One of the key enzymes in estrogen synthesis is aromatase. Inhibiting this pathway at several points is a promising idea for the treatment of endometriosis. The third generation of aromatase inhibitors is becoming more potent in efficacy, with fewer side effects than previous generations, but cotreatment with other hormones is needed to inhibit ovarian stimulation. Other components that promote estrogen synthesis such as COX-2 can also be potentially targeted. Selective estrogen-receptor modulators could also be interesting in view of their tissue-specific effect. However, all these new drugs are still in an early phase of development. At present, it is too early to conclude that aromatase inhibitors, COX-2 inhibitors or selective estrogen-receptor modulators really present any added value compared with the existing drugs that can be used to achieve hormonal suppression in the medical treatment of endometriosis.

Reducing the risk of early recurrence in hormone-responsive breast cancer

Following primary treatment for early breast cancer, systemic adjuvant therapy is given to reduce the risk of recurrence by targeting any undetectable micrometastatic deposits. Adjuvant systemic treatment may include endocrine therapy, chemotherapy and antibody therapy, depending on the presence or absence of hormone receptors, HER2 status and the estimated risk of relapse. In recent years, an increasing number of tumor characteristics have been identified that influence the risk of relapse and the likelihood of achieving the desired outcome with a given therapy. Hence, choosing the optimum therapy for early breast cancer is becoming an increasingly complicated task. Decision tools have been developed that can be used by physicians to select the most appropriate therapy on an individual basis. Treatment recommendations are, therefore, based on available data from a large number of sources. Hormone-receptor positivity (HR+) is the primary factor when considering whether or not patients should receive adjuvant endocrine therapy. For several decades, tamoxifen has been the gold standard of endocrine therapy, and has significantly reduced recurrences and deaths among the millions of women with HR+ breast cancer worldwide. However, prolonged use of tamoxifen is associated with potentially life-threatening side effects, and resistance is a common problem. In fact, many women will experience disease relapse while on tamoxifen. In particular, the peak of early relapses that occurs in the first 2-3 years after surgery is not prevented by tamoxifen. The third-generation aromatase inhibitors (AIs), letrozole, anastrozole and exemestane, have recently been shown to significantly improve outcomes compared with tamoxifen in large, randomized, controlled trials; however, how the AIs should be incorporated into adjuvant therapy to optimize outcomes requires further investigation. Clinical differences between the AIs, and whether tumor estrogen/progesterone receptor status and HER2 overexpression affect the response to AI therapy, are among the questions that remain to be answered. Ongoing and future studies will help to address these questions and, together with improved patient and disease profiling, will help physicians to optimize adjuvant treatment for individual patients.

2006 POSTER The potential role of bone derived cells in the development of breast cancer metastases

Polymorphisms in the CYP19A1 (aromatase) gene have been reported to influence disease-free survival and the incidence of musculoskeletal complaints in patients taking aromatase inhibitors (AIs) for estrogen receptor positive (ER +) breast cancer. Bone loss and fractures are well-recognized complications from AI therapy. The objective of this study is to determine the influence of polymorphisms in the CYP19A1 gene on bone loss among patients taking aromatase inhibitors for ER + breast cancer.The subjects consisted of 97 postmenopausal women with ER + breast cancer who were initiated on third-generation AIs. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry at baseline and at 6 and 12 months. Twenty-four hour urine N-telopeptide (NTX) was measured by Elisa and serum estradiol was measured by ultrasensitive radioimmunoassay at baseline, and at 6 months. Genotyping was done by Taqman SNP allelic discrimination assay.Women with the AA genotype for the rs700518 (G/A at Val80) developed significant bone loss at the lumbar spine and the total hip at 12 months relative to patients carrying the G allele (GA/GG); both p = 0.03. There was a borderline greater increase in urinary NTX in those with the AA genotype compared to patients with the G allele, p = 0.05; but no significant difference in changes in estradiol levels among the genotypes.Patients with the AA genotype for the rs700518 polymorphism in the CYP19A1 gene are at risk for AI-associated bone loss and deserve close follow-up during long-term AI therapy.

Safety profiles of tamoxifen and the aromatase inhibitors in adjuvant therapy of hormone-responsive early breast cancer

Adjuvant endocrine therapy plays an important role in the management of hormone-receptor-positive early breast cancer, and has increased life expectancy for millions of women. Many patients receive adjuvant treatment for at least 5 years following tumor resection, hence good long-term safety is important for endocrine agents to gain widespread acceptance. Tamoxifen has been used as adjuvant therapy for early breast cancer for many years, and safety data have been well documented, but a poor risk:benefit profile limits treatment duration to 5 years. Increased efficacy over tamoxifen and good tolerability have recently made the third-generation aromatase inhibitors (AIs) the first-choice agents for adjuvant endocrine therapy; however, it is currently not known whether AI therapy, like tamoxifen, will be limited to 5 years. Many side effects of endocrine therapy, such as hot flushes and mood disturbances, are related to estrogen deprivation and are common to tamoxifen and AIs, reflecting the mechanism of action of these drugs. In addition, tamoxifen has estrogenic effects that are beneficial in some tissues: tamoxifen lowers serum cholesterol levels and protects against bone loss and cardiovascular disease, but is also associated with potentially life-threatening side effects, such as endometrial cancer and thromboembolic disease. As AIs lack estrogenic activity, they are not associated with these serious adverse events. Clinical trials comparing AIs with tamoxifen in the adjuvant setting have shown that AIs are well tolerated and are associated with a lower incidence of gynecological symptoms and hot flushes than tamoxifen. However, AIs are associated with musculoskeletal side effects, such as arthralgia, myalgia and bone loss, but these events are preventable or manageable. The effects of AIs on lipid metabolism and the cardiovascular system are still debatable, but placebo-controlled trials provide no evidence to suggest that AIs adversely affect these systems. Furthermore, the AIs allow women to maintain a good quality of life, comparable with women receiving tamoxifen or placebo, and are a cost-effective therapeutic option. Ongoing trials will provide more information regarding the long-term effects of AI therapy and will provide comparative data on the efficacy and safety of the different AIs, thereby helping to determine the optimal treatment strategy for these highly effective and well-tolerated drugs.

Panorama actual de los inhibidores de la aromatasa en la inducción de la ovulación

El panorama actual de la inducción de la ovulación en el tratamiento de la infertilidad está cambiando debido a la introducción reciente en este campo de los inhibidores de la aromatasa de tercera generación (IA). Estos agentes han mostrado su eficacia como inductores de la ovulación, mediante la inhibición de la aromatasa que convierte los andrógenos en estrógenos, necesarios para el desarrollo y la maduración folicular. Este mecanismo de acción hace a los IA ventajosos frente al citrato de clomifeno, por carecer de efectos antiestrogénicos sobre el endometrio y el moco cervical. Presentamos una revisión de los tópicos más importantes con base en estudios publicados acerca del uso clínico de los IA.

Interaction between body mass index and bone turnover during aromatase inhibition: Evidence from the letrozole (L), exemestane (E), and anastrozole (A) pharmacodynamics (LEAP) trial

560 Background: High body mass index (BMI) protects against postmenopausal osteoporotic fracture, mediated in part by higher endogenous levels of oestradiol. Third-generation aromatase inhibitors (AIs) show superior efficacy and tolerability than tamoxifen in the adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer. We examined the interactions between BMI and bone turnover during treatment with 3 aromatase inhibitors in the LEAP trial, an open, randomized, pharmacodynamic study in postmenopausal women. Methods: Healthy volunteers from the UK and Hungary with normal bone density and BMI between 18 and 34 kg/m2 were randomized to receive A (1 mg/day), L (2.5 mg/day), or E (25 mg/day) orally, once daily for 24 weeks. Effects on bone resorption (log transformed serum C-telopeptide crosslinks, CTX) and bone formation (bone alkaline phosphatase and propeptide of type I procollagen, PINP) were compared. Changes in biochemical markers of bone resorption and formation during treatment were all statistically inter- correlated (p<0.01) with no notable differences between the 3 agents studied, so that the groups were pooled for analysis. Spearman correlation coefficients and the p-values were computed. Results: A total of 90 participants were evaluable at baseline and at 24 weeks (29 A, 29 L, 32 E). As expected, baseline BMI correlated with pre-treatment circulating endogenous oestradiol (r=0.28, p=0.007) and both BMI and oestradiol negatively correlated with baseline serum CTX (r=-0.32, p=0.0025 and r=-0.35, p=0.0007 respectively) and PINP (r=-0.30, p=0.004 and r=-0.26, p=0.016 respectively). Baseline BMI and oestradiol were significantly correlated with the increase in serum CTX (r=0.26, p=0.015 and r=0.23, p=0.032 respectively) and BMI also correlated significantly with the increase in serum PINP (r=0.23, p=0.030). Conclusions: Steroidal and non-steroidal AIs increase bone turnover with the greatest increase in women with high BMI and higher oestradiol levels at baseline. As increased bone turnover is an independent risk factor for fracture, a high BMI may not confer a reduced fracture risk in the setting of AI use in early breast cancer. No significant financial relationships to disclose.

The National Cancer Institute of Canada Clinical Trials Group MAP.3 Trial: An International Breast Cancer Prevention Trial

Several large phase III trials have demonstrated that tamoxifen-and more recently, raloxifene-can effectively reduce the incidence of invasive breast cancer by 50%. However, these selective estrogen receptor modulators can also be associated with several rare, but serious, adverse events. Recently, the third-generation aromatase inhibitors (AIS) have demonstrated excellent efficacy in adjuvant breast cancer trials, and they show particular promise in the breast cancer prevention setting. The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) has developed a randomized phase III study to determine the efficacy of an ai (exemestane) to reduce the incidence of invasive breast cancer in postmenopausal women at an increased risk for developing breast cancer. The NCIC CTG map.3 (ExCel) trial is a double-blind placebo-controlled multicentre, multinational trial. Based on the known preclinical and clinical profile of the ais, a greater reduction in breast cancer incidence with fewer side effects is hypothesized with this class of agents than with tamoxifen or raloxifene.

New experimental models for aromatase inhibitor resistance

Clinical trials have demonstrated the importance of aromatase inhibitor (AI) therapy in the effective treatment of hormone-dependent breast cancers. In contrast to tamoxifen, an antagonist of the estrogen receptor (ER), AIs have shown to be better tolerated along with decreased recurrence rates of the disease. Currently, three third-generation AIs are being used: exemestane, letrozole, and anastrozole. Our laboratory is attempting to understand several aspects of AI functionality. In this paper, we first review recent findings from our structure–function studies of aromatase as well as the molecular characterization of the interaction between AIs and aromatase. Based on these studies, we propose new evidence for the interaction of letrozole and exemestane with aromatase. In addition, we will discuss recent results generated from our AI-resistant cell lines. Our laboratory has generated MCF-7aro cells that are resistant to letrozole, anastrozole, exemestane, and tamoxifen. Basic functional characterization of aromatase and ERα in these resistant cell lines has been done and microarray analysis has been employed in order to better understand the mechanism responsible for AI resistance on a genome-wide scale. The results generated so far suggest the presence of at least four types of resistant cell lines. Overall, the information presented in this paper supplements our understanding of AI function, and such information can be valuable for the development of treatment strategies against AI resistant breast cancers.

Exemestane after non-steroidal aromatase inhibitors for post-menopausal women with advanced breast cancer

A retrospective analysis was performed on 31 consecutive locally advanced or metastatic breast cancer patients who commenced exemestane 25mg/d orally following previous treatment with Tamoxifen and a non-steroidal third-generation aromatase inhibitor (AI). Patients were seen 3 monthly until clinical or radiological disease progression. Median age was 64 years (range 34-90 yrs). The average number of recurrences before starting exemestane was three (range 1-6). There were two complete responses (CR), four partial responses (PR), 12 with stable disease (SD) and 12 with progressive disease (PD). Objective response rate (CR+PR) was 19.4% and overall clinical benefit (CR+PR+SD >or= 24 weeks) was 54.8%. The median durations of objective response and overall clinical benefit were 18 and 14 months, respectively. This data support the anti-tumour activity of exemestane 25mg daily in patients with locally advanced and/or metastatic breast cancer who have been previously exposed to non-steroidal AIs and Tamoxifen.

Letrozole Treatment of Precocious Puberty in Girls with the McCune-Albright Syndrome: A Pilot Study

Girls with McCune-Albright syndrome (MAS) and related disorders have gonadotropin-independent precocious puberty due to estrogen secretion from ovarian cysts. Their puberty does not respond to GnRH agonist therapy, and short-acting aromatase inhibitors have had limited effectiveness. Our objective was to assess the effectiveness of the potent, third-generation aromatase inhibitor letrozole in decreasing pubertal progression in girls with MAS and to assess the response of indices of bone turnover associated with the patients' polyostotic fibrous dysplasia. Subjects were evaluated at baseline and every 6 months for 12-36 months while on treatment with letrozole 1.5-2.0 mg/m(2).d. This was an open-label therapeutic trial at a single clinical center. Patients included nine girls aged 3-8 yr with MAS and/or gonadotropin-independent puberty. Measures included rates of linear growth, bone age advance, mean ovarian volume, estradiol, episodes of vaginal bleeding, and levels of the indices of bone metabolism: serum osteocalcin, alkaline phosphatase, urinary hydroxyproline, pyridinoline, deoxypyridinoline, and N-telopeptides. Girls had decreased rates of growth (P < or = 0.01) and bone age advance (P < or = 0.004) and cessation or slowing in their rates of bleeding over 12-36 months of therapy. Mean ovarian volume, estradiol, and indices of bone metabolism fell after 6 months (P < or = 0.05) but tended to rise by 24-36 months. Uterine volumes did not change. One girl had a ruptured ovarian cyst after 2 yr of treatment. This preliminary study suggests that letrozole may be effective therapy in some girls with MAS and/or gonadotropin-independent precocious puberty. Possible adverse effects include ovarian enlargement and cyst formation.

Recent perspectives of endocrine therapy for breast cancer

The choice of endocrine therapy for breast cancer depends on the menopausal status and stage of disease. Endocrine therapy remains the first choice and most important component in the treatment of hormone sensitive non-life threatening advanced breast cancer. In premenopausal women with metastatic disease, the combination of a luteinizing hormone-releasing hormone (LH-RH) agonist plus tamoxifen is reasonable as first-line endocrine therapy. In postmenopausal patients with recurrent disease progressing after or during adjuvant tamoxifen, third-generation aromatase inhibitors (AIs) are the preferred first-line endocrine treatment. Many premenopausal and postmenopausal women with hormone responsive breast cancer benefit from sequential use of endocrine therapies at the time of disease progression. Recent clinical trials designs have been implemented, employing AIs as monotherapy in postmenopausal breast cancer patients, as first-line adjuvant therapy, and in sequence either 2-3 or 5 years, with initial tamoxifen. Emerging results from these trials indicate an advantage to patients for any of these strategies, and most international guidelines now suggest the use of an AI in the adjuvant setting in postmenopausal women. The use of endocrine treatment for metastatic and early breast cancer will be reviewed here.

Adjuvant aromatase inhibitors in breast cancer therapy: significance of musculoskeletal complications

Aromatase inhibitors, which offer profound suppression of estrogen synthesis, have been introduced as long-term adjuvant therapeutic agents for postmenopausal women with breast cancer. Compared with tamoxifen treatment, which has long been the standard of care in anti-estrogen therapy, third-generation aromatase inhibitors offer superior efficacy with regard to disease-free survival rates. The aromatase inhibitors anastrozole, letrozole and exemestane have a different toxicity profile from tamoxifen and are relatively free of some of the side effects associated with tamoxifen, such as deep vein thrombosis and uterine malignancies. They can, however, cause bone and joint pain (arthralgia), as well as the loss of bone mineral density and an increased incidence of fractures. These events appear to arise as class effects for the aromatase inhibitors, as they occur with all members of this structurally and mechanistically diverse group of drugs. Here we summarize the latest data on the efficacy of aromatase inhibitors and their effects on the risk of arthralgia and other musculoskeletal complications, notably from five ongoing clinical trials comparing aromatase inhibitors with tamoxifen or placebo.

Second- and Third-generation Aromatase Inhibitors as First-line Endocrine Therapy in Postmenopausal Metastatic Breast Cancer Patients: A Pooled Analysis of the Randomised Trials

Second- and Third-generation Aromatase Inhibitors as First-line Endocrine Therapy in Postmenopausal Metastatic Breast Cancer Patients: A Pooled Analysis of the Randomised Trials

Aromatase inhibitors: a safety comparison

For almost three decades, tamoxifen has been the mainstay of hormonal therapy in breast cancer patients, but now the third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, are emerging as potential alternatives, associating greater clinical efficacy with a more favourable overall safety profile than tamoxifen. AIs are associated with a lower incidence of thromboembolic events and vaginal bleeding compared with tamoxifen, although they are known to affect bone turnover and possibly lipid metabolism. As the available AIs have similar efficacy, it is likely that safety and tolerability profiles will have an impact on agent selection in clinical practice. Therefore, it is important that differences in the safety profiles of the third-generation AIs are understood.

Letrozole in advanced breast cancer: the PO25 trial

Tamoxifen has been a standard first-line endocrine therapy for post-menopausal women with hormone-responsive advanced breast cancer, but more than half of patients fail to respond and time to progression is less than 12 months in responders. The third-generation aromatase inhibitors were developed to provide more effective alternatives to tamoxifen. In the Femara Study PO25, post-menopausal women with advanced breast cancer were randomized to receive letrozole 2.5 mg (n = 453) or tamoxifen 20 mg (n = 454) given orally daily until progressive disease occurred. Patients were permitted to cross over to the other treatment at progression. In the primary efficacy analysis, median time to progression (TTP) was significantly longer with letrozole than with tamoxifen (9.4 months vs. 6.0 months, respectively; P < 0.0001). The objective response rate (ORR) was significantly higher for letrozole than for tamoxifen (32% vs. 21%; P = 0.0002). Prospectively planned analyses of the intent-to-treat population showed that letrozole significantly improved overall survival (OS) compared with tamoxifen over the first 24 months of the trial. An exploratory analysis of patients, who did not cross over, indicated a median OS benefit of 14 months for letrozole compared with tamoxifen. Letrozole is the only third-generation aromatase inhibitor that has demonstrated significant improvements in ORR, TTP, and early OS.

The Prevention and Management of Distant Metastases in Women with Breast Cancer

About one-third of all women diagnosed with breast cancer face the risk of recurrence, which can occur at any stage of disease, observation time, and after any treatment modality. Most recurrence comes in the form of distant metastasis, which is the major cause of death in women with breast cancer. Treatments shown to decrease the risk of breast cancer recurrence, especially distant metastasis, will likely produce a survival benefit and a potentially significant improvement in quality of life in women with early breast cancer. New third-generation aromatase inhibitors (anastrozole, exemestane, and letrozole) that have been shown to be well tolerated have the potential to contribute to benefits beyond those seen with tamoxifen.

Aromatase Inhibitors in the Adjuvant Treatment of Postmenopausal Women with Early Breast Cancer: Putting Safety Issues into Perspective

Tamoxifen has been the gold standard adjuvant therapy for the treatment of postmenopausal women with hormone-receptor-positive (HR+) early breast cancer for many years. Tamoxifen treatment is limited to 5 years because of the development of de novo and acquired resistance, and an ongoing risk of adverse events, including endometrial cancer, thromboembolic events, and gynecological symptoms with long-term use. The third-generation aromatase inhibitors (AIs), letrozole, anastrozole, and exemestane, are displacing tamoxifen as the first-choice therapy for HR+ early breast cancer, and are now recommended as the preferred therapy by national and international guidelines. Recent randomized trials have demonstrated that the AIs are more effective than tamoxifen in preventing disease recurrence when used in substitution and sequential strategies in the early adjuvant setting, and letrozole has been shown to be more effective than placebo in the extended adjuvant setting (after 5 years of tamoxifen therapy). Trial safety data show that the overall tolerability of AIs is similar to that of tamoxifen, with adverse events being predictably characteristic of estrogen deprivation; however, some important differences in adverse event profiles between tamoxifen and the AIs have been demonstrated. In addition to antiestrogenic effects, tamoxifen acts as an estrogen agonist in some tissues, which can lead to serious side effects not associated with the AIs, which prevent estrogen biosynthesis. A lower incidence of gynecological and thromboembolic events is observed in patients taking AIs, and fewer cases of endometrial cancer are seen compared with tamoxifen. Adverse events that are more frequent with adjuvant AI therapy compared with tamoxifen include arthralgia and myalgia, bone loss, and effects on the cardiovascular system and blood lipids. The effects of AIs on bone are predictable and may be easily managed, where necessary, with bisphosphonates. Studies examining the effects of AIs on the cardiovascular system and lipid profiles, including in the extended adjuvant setting, suggest that these adverse events may be due to the absence of a protective effect of tamoxifen rather than true AI toxicity. Further studies are required to determine the long-term safety of AI therapy in postmenopausal women with HR+ early breast cancer.

Estrogen Receptor Modulators and Down Regulators

Endocrine treatments have been used in breast cancer since 1896, when Beatson reported on the results of oophorectomy for advanced breast cancer. In the second half of the last century, different endocrine-based compounds were developed and, in this review, the role of the selective estrogen receptor modulators (SERMs) and selective estrogen receptor down regulators (SERDs) in the postmenopausal setting are discussed. Tamoxifen is the most investigated and most widely used representative of these agents, and has been introduced in the advanced disease, in the neoadjuvant and adjuvant setting, and for the prevention of the disease. Its role has been challenged in recent years by the introduction of third-generation aromatase inhibitors that have proven higher activities than tamoxifen with different toxicity patterns. Several other SERMs have been investigated, but none have been clearly superior to tamoxifen. SERDs act as pure estrogen antagonists and should compare favourably to tamoxifen. For the time being, they have been used in the treatment of advanced breast cancers and their role in other settings still needs investigation. The increased use of aromatase inhibitors as first-line endocrine therapy has resulted in new discussions regarding the role that tamoxifen and other SERMs or SERDs may play in breast cancer. The sequencing of endocrine therapies in hormone-sensitive breast cancer remains a very important research issue.

Update on the MA.17 extended adjuvant trial

For women with early breast cancer, a substantial risk of relapse remains after surgical resection of the primary tumor, despite adjuvant therapy. Adjuvant endocrine therapy with tamoxifen has been used for many years in the treatment of hormone-receptor-positive (HR+) disease, but exposure to the agent is limited to 5 years due to an unfavorable risk:benefit profile in later years. Despite the beneficial carry-over effects of tamoxifen, the majority of breast cancer recurrences and deaths occur after completion of adjuvant tamoxifen, that is, more than 5 years after initial diagnosis. Hence, additional endocrine therapy could greatly improve outcomes for women with HR+ early breast cancer, but until recently, no agent had been shown to provide a significant benefit over no further treatment. The first interim analysis of the NCIC CTG MA.17 trial showed that the third-generation aromatase inhibitor, letrozole, significantly reduced the risk of relapse, including distant metastases, compared with placebo in women who remained disease-free for up to 3 months after completion of standard adjuvant tamoxifen. On the basis of these results, the trial was stopped and unblinded. Final analysis confirmed these findings and also showed that letrozole significantly improved overall survival in patients with node-positive disease at diagnosis. Retrospective analysis of MA.17 data has shown that the benefit achieved with letrozole increases with the duration of therapy, at least up to 48 months, raising important questions regarding the optimal duration of extended adjuvant letrozole. Additional retrospective analyses investigating the impact of estrogen- and progesterone-receptor status on response to therapy, and whether letrozole is effective following a prolonged treatment-free interval after stopping tamoxifen, are ongoing, and will help to optimize the use of letrozole in women who have completed tamoxifen.

Aromatase inhibitors: effective endocrine therapy in the early adjuvant setting for postmenopausal women with hormone-responsive breast cancer

Early breast cancer now has a relatively good prognosis, with many affected women surviving for over a decade. In hormone-receptor-positive (HR+) disease, adjuvant tamoxifen therapy has had a particularly strong impact on outcomes over the past 30 years, preventing approximately half of all expected recurrences and a third of all breast cancer deaths. For many years, adjuvant tamoxifen for 5 years was the standard treatment for HR+ disease. However, de novo and acquired resistance is common, and many patients will experience a relapse while on tamoxifen, indicating the need for more effective agents to treat HR+ breast cancer. Furthermore, tamoxifen is associated with potentially life-threatening side effects, including thromboembolic disease and endometrial cancer which, together with decreasing efficacy, limit tamoxifen to 5 years. In recent years, the third-generation aromatase inhibitors (AI) have demonstrated superior efficacy to tamoxifen as adjuvant therapy for HR+ early breast cancer in postmenopausal women. In large, randomized, controlled trials, upfront substitution of tamoxifen with an AI for 5 years or switching to an AI after 2–3 years of tamoxifen have been shown to significantly reduce recurrences compared with 5 years of tamoxifen. The benefits of sequential endocrine therapy with tamoxifen followed by an AI and vice versa are unconfirmed. Adjuvant AI therapy was well tolerated, with side effects being generally predictable and more manageable than those associated with tamoxifen. Whether clinical differences exist between anastrozole, letrozole and exemestane has yet to be confirmed in head-to-head trials, but available data suggest that letrozole may be particularly effective in patients with node-positive disease or those who have received adjuvant chemotherapy, that is, patients at increased risk of an early relapse. Furthermore, upfront letrozole, but not anastrozole, significantly reduced distant metastases, a well-recognized predictor of breast cancer death. The optimal treatment regimen requires clarification, and ongoing studies will provide further information regarding the optimum treatment strategy to gain the greatest clinical impact from the AIs in the adjuvant setting.