Extended adjuvant endocrine therapy of early breast cancer

Women who are diagnosed with early breast cancer remain at considerable risk of recurrence over the next several decades, even if their tumors were small and lymph nodes were negative, and despite receiving standard adjuvant therapy. A majority of breast cancers are hormone (estrogen) receptor-positive and amenable to endocrine therapy, and for those women five years of the selective estrogen receptor modulator tamoxifen is standard therapy. Longer treatment of node-negative patients with tamoxifen may reduce survival benefits, however, possibly due to tamoxifen resistance and emerging receptor agonist activity of that drug. Aromatase inhibitors, which indirectly prevent estrogen stimulation of breast cancer by suppressing whole-body estrogen synthesis in post-menopausal women, are being investigated as alternative, or complementary, therapy to adjuvant tamoxifen in those women: as an alternative to five years of tamoxifen, sequenced with two to three years of tamoxifen, or following five years of tamoxifen. The strategy to extend the benefits of adjuvant therapy beyond a standard course of tamoxifen, using the aromatase inhibitor letrozole, was explored in a large trial, MA.17. Compared with women who received placebo, those who were treated with letrozole experienced a significant 43% reduction in their residual risk of recurrence. This effect was seen regardless of nodal status. Based on the long-term risk of most women with early breast cancer and the MA.17 trial results, the extended adjuvant letrozole may benefit many of those women who are disease-free after five years of tamoxifen. This review is based on a literature search of databases including MEDLINE/PubMed, San Antonio Breast Cancer Symposium, and the Annual Meeting of the American Society of Clinical Oncology, up to and including August 2005, with information selected for its relevance to adjuvant therapy of breast cancer with endocrine therapy only.     

Aromatase inhibitors in early breast cancer therapy: a variety of treatment strategies

Until recently, standard endocrine therapy for estrogen receptor-positive early breast cancer in the preoperative neoadjuvant and postoperative adjuvant settings was the selective estrogen receptor modulator tamoxifen. An alternate therapeutic approach is to suppress total-body estrogen synthesis using an aromatase inhibitor. The highly potent and specific third-generation aromatase inhibitors (anastrozole, exemestane and letrozole) have consistently demonstrated improved efficacy over tamoxifen in large randomised neoadjuvant and adjuvant clinical trials. As neoadjuvant therapy, compared with tamoxifen, all three aromatase inhibitors significantly improved breast-conserving surgery rates, but only letrozole achieved a significantly higher overall response rate. These agents have also been evaluated in three adjuvant strategies: instead of tamoxifen for 5 years, sequenced after 2 – 3 years of tamoxifen, or as extended adjuvant therapy following a full 5-year course of tamoxifen. In all cases, the aromatase inhibitor was significantly more effective in reducing the risk of recurrence, compared with tamoxifen in the first two approaches and with placebo or no treatment as extended therapy. Long-term aromatase inhibitor treatment is associated with less endometrial cancer, thromboembolic events and strokes than tamoxifen, but more musculoskeletal disorders and bone loss. Further investigation is focusing on identification of the patient subgroups most likely to benefit from each of these adjuvant therapy options.     

Aromatase inhibitors in early breast cancer therapy: a variety of treatment strategies

Until recently, standard endocrine therapy for estrogen receptor-positive early breast cancer in the preoperative neoadjuvant and postoperative adjuvant settings was the selective estrogen receptor modulator tamoxifen. An alternate therapeutic approach is to suppress total-body estrogen synthesis using an aromatase inhibitor. The highly potent and specific third-generation aromatase inhibitors (anastrozole, exemestane and letrozole) have consistently demonstrated improved efficacy over tamoxifen in large randomised neoadjuvant and adjuvant clinical trials. As neoadjuvant therapy, compared with tamoxifen, all three aromatase inhibitors significantly improved breast-conserving surgery rates, but only letrozole achieved a significantly higher overall response rate. These agents have also been evaluated in three adjuvant strategies: instead of tamoxifen for 5 years, sequenced after 2-3 years of tamoxifen, or as extended adjuvant therapy following a full 5-year course of tamoxifen. In all cases, the aromatase inhibitor was significantly more effective in reducing the risk of recurrence, compared with tamoxifen in the first two approaches and with placebo or no treatment as extended therapy. Long-term aromatase inhibitor treatment is associated with less endometrial cancer, thromboembolic events and strokes than tamoxifen, but more musculoskeletal disorders and bone loss. Further investigation is focusing on identification of the patient subgroups most likely to benefit from each of these adjuvant therapy options.     

Never too late: reducing late breast cancer relapse risk

ABSTRACT

Background: Breast cancer is the most common cancer diagnosed in Europe, with an estimated 429 900 new cases diagnosed in 2006. For over 20 years, tamoxifen was the standard adjuvant (postoperative) endocrine treatment for hormone receptor-positive (i.e., endocrine-responsive) early breast cancer. Yet, even after the first 5 years, patients with hormone receptor-positive tumours are at risk of relapse. Particularly in endocrine-responsive disease, most instances of relapse and breast cancer mortality occur after the first 5 years.

Scope: Extended adjuvant aromatase inhibitor therapy (EAT) now offers postmenopausal women the opportunity to further protect themselves against late relapse.

Methods: This review summarises the clinical evidence and gives practical recommendations for discussing EAT with patients. Relevant information on patients receiving extended or late extended adjuvant endocrine therapy was obtained from databases and congress websites. The most substantial evidence for EAT is provided by the MA.17 trial using letrozole, with similar results obtained from smaller studies using anastrozole or exemestane.

Findings: Extended adjuvant letrozole reduced the risk of recurrence by 42% and the risk of distant metastases by 40%, it was well tolerated compared to placebo; among lymph node-positive patients, overall survival was significantly improved. Ideally, EAT should be started within 3 months of finishing tamoxifen therapy, and evidence supports its use for at least 4 years, showing increasing benefit with longer treatment duration. It is also effective, even after a longer time period, following completion of tamoxifen therapy. When deciding whether or not to use EAT after tamoxifen, clinicians and patients should consider the residual risk of relapse, comorbidities and individual preferences.     

Cost effectiveness of extended adjuvant letrozole in postmenopausal women after adjuvant tamoxifen therapy: the UK perspective

BACKGROUND: MA17 was a randomised placebo-controlled trial of letrozole 2.5 mg/day in 5187 estrogen receptor-positive, 50% node-negative, postmenopausal women (median age 62 years at enrollment) with early breast cancer, post-5 years' adjuvant tamoxifen therapy. The objective of this evaluation was to extrapolate the findings from the MA17 trial to estimate the lifetime cost effectiveness of letrozole in this setting. METHODS: A Markov model was used to estimate the incremental cost per QALY gained with extended adjuvant letrozole versus no therapy. Probabilities of disease progression and death were estimated using data from the MA17 study and other secondary sources. Costs of breast cancer care (letrozole therapy, surveillance, recurrences, terminal care) and treatment of osteoporosis and utilities were derived from literature. A full probabilistic sensitivity analysis was undertaken. The analysis was conducted from the perspective of the UK National Health Service (NHS) and cost estimates reflect 2004 values. All costs and outcomes were discounted at 3.5%. RESULTS: Extended adjuvant letrozole resulted in a gain of 0.36 QALYs per patient (13.66 vs 13.30 with no therapy). These benefits were obtained at an additional expected lifetime cost of 3732 pounds per patient (10,833 pounds letrozole vs 7101 pounds with no therapy). Cost effectiveness was estimated at 10,338 pounds per QALY gained (95% CI 5276, 43,828). The results were robust to sensitivity analyses. CONCLUSION: Five years of letrozole therapy appears to be cost effective from the NHS perspective and should be considered in women with early breast cancer, following tamoxifen adjuvant therapy.     

Letrozole : in postmenopausal hormone-responsive early-stage breast cancer

Letrozole is a highly selective, nonsteroidal, third-generation aromatase inhibitor approved for first-line and extended adjuvant therapy in postmenopausal women with hormone-responsive, early-stage breast cancer. Binding of letrozole to the haeme component of the cytochrome P450 subunit of aromatase inhibits estrogen biosynthesis throughout the body. As first-line adjuvant therapy in approximate, equals 8000 postmenopausal women with hormone-responsive, early-stage breast cancer, once-daily letrozole 2.5mg significantly prolonged disease-free survival (DFS; primary endpoint) and reduced the risk of relapse at distant sites relative to once-daily tamoxifen 20mg in the ongoing Breast International Group 1-98, double-blind, multinational trial. The median duration of follow-up for this primary core analysis was 25.8 months. Extended adjuvant therapy with once-daily letrozole 2.5mg significantly prolonged DFS relative to placebo treatment at a median follow-up of 30 months (primary endpoint) in the MA-17 trial in approximate, equals 5000 postmenopausal women who were disease free after 4.5-6 years of tamoxifen therapy for hormone-responsive, early-stage breast cancer. Letrozole treatment for up to 5 years was generally well tolerated in this clinical setting. As first-line treatment, relative to tamoxifen, letrozole was associated with a significantly lower incidence of venous thromboembolitic events, vaginal bleeding, hot flushes and night sweating, whereas the incidence of cardiac failure, bone fractures and arthralgia was higher in letrozole recipients.     

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: 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.     

来曲唑治疗绝经后妇女乳腺癌疗效的系统评价

目的:系统评价来曲唑治疗绝经后妇女乳腺癌的疗效。方法:采用Cochrane系统评价方法,检索Cochrane图书馆,PubMed、CNKI及CBMdisc等数据库。纳入来曲唑治疗绝经后妇女乳腺癌的随机对照试验(RCT),并逐篇进行质量评价和资料提取。统计学数据采用RevMan5.0软件进行处理。结果:共纳入6个RCT,患者6316例。术后辅助内分泌治疗中,来曲唑在增加无病进展存活率方面,显示优于他莫昔芬的疗效,但二者总体生存率差异无统计学意义;在复发或转移后的解救治疗中,来曲唑在总体生存率、无病进展存活率、客观反应率方面,均显示优于他莫昔芬的远期疗效;在术前新辅助内分泌治疗中,来曲唑在增加客观反应率方面,显示优于他莫昔芬的疗效。结论:目前证据表明,来曲唑在各种乳腺癌内分泌治疗方式中,均显示出优于他莫昔芬的疗效。期待更多高质量、大样本的RCT,以提供更可靠的证据。     

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.     

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.     

Fulvestrant: a new type of estrogen receptor antagonist for the treatment of advanced breast cancer

Postmenopausal women with hormone receptor- positive tumors are candidates for endocrine treatment. Current treatment options include the selective estrogen receptor modulators (e.g., tamoxifen and toremifene), which inhibit estrogen receptor signaling, and the aromatase inhibitors (e.g., anastrozole and letrozole), which prevent the conversion of androgens into estrogen in postmenopausal women. As most patients eventually become resistant to endocrine agents, there is a need for new treatments that are effective, well tolerated and lack cross-resistance with currently available therapies. This review describes the development of fulvestrant (Faslodex), a new type of endocrine agent, which is an estrogen receptor antagonist with no agonist effects. Phase III clinical trials have found that fulvestrant is as effective and well tolerated as anastrozole for treating postmenopausal patients with advanced breast cancer who have progressed on one prior endocrine therapy. In addition, fulvestrant has first-line efficacy similar to that of tamoxifen in patients with estrogen receptor-positive and/or progesterone receptor-positive breast cancer. Moreover, in a compassionate-use program, it has become clear that fulvestrant is not cross-resistant with other therapies. Therefore, fulvestrant is a versatile new treatment option for postmenopausal women with advanced breast cancer who have progressed on prior endocrine therapy.     

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.     

Adjuvant hormone therapy for breast cancer: alternatives to tamoxifen

(1) After surgical excision of hormone-receptor-positive non metastatic breast cancer in postmenopausal women, a meta-analysis of 55 trials has shown that adjuvant tamoxifen, 20 mg/day for 5 years, reduces the risk of relapse by 8% and the risk of death by 5% (absolute values). The benefit of treatment beyond 5 years remains to be established. (2) Preliminary four-year results from a double-blind randomised controlled trial comparing anastrozole with tamoxifen (ATAC trial) indicated an advantage for anastrozole in reducing the risk of relapse. There was no difference in survival rate. Women taking anastrozole experienced more sexual dysfunction and an increased risk of osteoporotic fractures, whereas tamoxifen was associated with an increased risk of thrombosis and endometrial cancer. The trial's methodology is controversial, however, and conclusions concerning the relative risk-benefit balances of these two drugs must await the full 5-year results. (3) A double-blind placebo-controlled trial of letrozole, prescribed after 5 years of adjuvant tamoxifen, was stopped early after a median follow-up of 2.4 years. When extrapolated to 4 years, the results suggest that letrozole reduced the risk of relapse (7%, compared to 13% with tamoxifen) but had no effect on survival. (4) A double-blind trial comparing tamoxifen with exemestane in 4742 women who had already received tamoxifen for two to three years showed a higher three-year disease-free survival rate with exemestane (91.5% versus 86.8%). Overall survival did not differ between the two groups. (5) Pending results of further clinical trials, tamoxifen remains the first-line adjuvant hormone therapy for most postmenopausal women with hormone-receptor-positive non metastatic breast cancer.     

Complete estrogen blockade for the treatment of metastatic and early stage breast cancer

Complete estrogen blockade has long been sought as a more effective means of controlling breast cancer compared with single agent endocrine therapy. This approach may be accomplished through the use of agents which reduce estrogen production combined with agents that prevent the activity of estrogen at the cellular level. For prostate cancer, another hormonally responsive malignancy, this approach has not been successful at improving survival compared with that achieved with single agent therapy. Preclinical information is contradictory for many promising combinations and may not reflect the true nature of in vivo interaction between agents. For premenopausal patients with metastatic breast cancer, the combination of a luteinising hormone-releasing hormone (LHRH) agonist and tamoxifen is clearly effective, but whether the combination is more effective than either single agent is still controversial. Similar response rates and overall survival were reported with goserelin or goserelin plus tamoxifen by Jonat et al. in 1 randomised, prospective study, but the addition of tamoxifen improved time to progression. A second trial comparing buserelin plus tamoxifen with either single agent reported superior efficacy in terms of response rates, disease-free survival and overall survival with combination therapy. A meta-analysis of 4 randomised trials making similar comparisons, demonstrated significant improvement in median overall survival, progression-free survival, response rate, and duration of response with the combination of a LHRH agonist (goserelin or buserelin) and tamoxifen in premenopausal breast cancer patients with metastatic disease. For postmenopausal women with metastatic breast cancer, the addition of an aromatase inhibitor to tamoxifen has yet to be prospectively compared to single agent therapy. Use of endocrine combinations in the treatment of early stage breast cancer is under investigation. Preliminary results of some of the ongoing adjuvant therapy trials indicate that the combination of a LHRH agonist and tamoxifen may have similar efficacy to cyclophosphamide, methotrexate, and fluorouracil chemotherapy in premenopausal women with estrogen receptor-positive tumour. Addition of LHRH agonist therapy in premenopausal patients with estrogen receptor-positive tumour who had maintained the ovarian function following chemotherapy [cyclophosphamide, doxorubicin (adriamycin), fluorouracil, and tamoxifen], also led to a reduction in the risk of recurrence. These studies have identified a sub-population of patients who may benefit from the addition of combination endocrine therapy. Overall, the issue is quite complex and the data from many ongoing trials are still awaited with anticipation to further delineate the role of complete estrogen deprivation in this disease.     

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

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.     

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.