Challenges in the endocrine management of breast cancer

The goal of endocrine therapy in breast cancer is to block the action of estrogen on the tumor cells either by inhibiting estrogen from binding to the specific estrogen receptor or by inhibiting its synthesis. Tamoxifen, a selective estrogen receptor modulator, is the standard endocrine treatment for hormone receptor-positive breast cancer, both in the adjuvant and metastatic settings. Tamoxifen inhibits the binding of estrogen to the receptor, resulting in inhibition of hormone action. However, as tamoxifen is also weakly estrogenic, it may not be optimally effective and increases the risk of endometrial cancer and stroke. Furthermore, patients may be refractory or may become resistant to tamoxifen treatment. Since aromatase inhibitors (AI) block the synthesis of estrogen and have no intrinsic estrogenic activity, they have the potential to be more effective than tamoxifen. Their different mechanism of action and chemical structures may also circumvent tamoxifen resistance. Consequently, AIs are currently being evaluated as an alternative to tamoxifen treatment. A preclinical model has recently been developed to compare the efficacy of AIs and antiestrogens in different treatment schemes and to assist in the design of clinical trials. Current studies with the MCF-7Ca xenograft model are exploring the effects of combination and sequential therapy on tumor growth. The efficacy of AIs in the treatment of hormone receptor-positive breast cancer was first demonstrated in five multicenter second-line trials enrolling several hundreds of postmenopausal patients with metastatic breast cancer who had failed tamoxifen treatment. More recently, anastrozole demonstrated efficacy at least equivalent to that of tamoxifen in first-line randomized, phase III clinical trials in postmenopausal women with hormone receptor-positive or unknown metastatic breast cancer, whereas letrozole demonstrated superiority. The steroidal AI exemestane is currently under evaluation. Letrozole is the only AI to have been studied in a randomized, phase III trial in the neoadjuvant setting. In this trial, more patients underwent breast-conserving surgery with letrozole than with tamoxifen. Smaller phase II studies also suggest that both anastrozole and exemestane are active in the neoadjuvant setting. Because neoadjuvant trials permit temporal sampling of breast tissue, substudies in the phase III trial with letrozole have examined the impact of such biomarkers as estrogen receptor, progesterone receptor and epidermal growth factor receptor family members, HER-1 and HER-2, on patient response. AIs are currently under evaluation in the adjuvant setting, and preliminary results of the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial have been reported. AIs have proven as safe as tamoxifen in trials in patients with metastatic breast cancer. Ongoing clinical trials in the adjuvant setting include companion studies of end-organ effects, particularly bone metabolism and lipid metabolism evaluations. Quality-of-life assessments are also parts of major clinical trials. A head-to-head quality-of-life assessment of anastrozole compared with letrozole demonstrated patient preference for letrozole. These assessments also clearly indicated the eagerness of patients to participate actively in treatment decisions     

Are all aromatase inhibitors the same? A review of the current evidence

Third-generation aromatase inhibitors (AIs)--letrozole, anastrozole, and exemestane--are challenging tamoxifen as the standard endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer. AIs suppress estrogen levels by inhibiting aromatase, the enzyme that catalyzes the final step of estrogen biosynthesis. Studies have shown that AIs are highly effective and safe in the treatment of advanced disease, and more recently, AIs have shown promise in the neoadjuvant, adjuvant, and extended adjuvant settings. However, all AIs are not equal. In direct comparisons with anastrozole, letrozole has demonstrated superior estrogen suppression and clinical response in patients with advanced metastatic breast cancer. In addition, letrozole is the only AI to demonstrate consistent superiority over tamoxifen in the neoadjuvant and first-line advanced breast cancer settings. This publication summarizes the available evidence for the efficacy of all 3 agents throughout the breast cancer continuum.     

Role of endocrine therapy in the neoadjuvant surgical setting

Most neoadjuvant (preoperative) therapy of breast cancer has involved the use of chemotherapy, but primary endocrine therapy has also been shown to be effective in postmenopausal women with estrogen receptor-positive tumors. Neoadjuvant therapy can reduce tumor volume, permitting surgery for otherwise inoperable tumors or allowing breast-conserving surgery rather than mastectomy for operable tumors. The preoperative treatment setting also allows for assessment and comparison of responses to different agents, which may then be used in the adjuvant therapy setting following surgery. Since tumor biopsies can be obtained before, during, and after preoperative therapy, the relationship between biomarkers and response or resistance to surgery can be investigated. In the Edinburgh Breast Unit, neoadjuvant endocrine therapy with aromatase inhibitors has been more successful than with tamoxifen. Recurrence rates following preoperative endocrine therapy and breast-conserving surgery have been acceptably low, provided that radiation therapy was also administered postoperatively. Both the probability of response to neoadjuvant letrozole or tamoxifen and the degree of tumor shrinkage increased as estrogen receptor expression increased, consistent with the results of other studies. Attempts to identify biomarkers of response to neoadjuvant endocrine therapy are under way, with early indications that reduced cell proliferation 14 days after initiation of treatment correlates with responses to tamoxifen.     

The evolving role of letrozole in the adjuvant setting: first results from the large, phase III, randomized trial BIG 1-98

Tamoxifen has been a standard adjuvant therapy, despite its limited 5-year efficacy window and risk of thromboembolism and endometrial malignancy. The potent aromatase inhibitor letrozole (Femara) has emerged as a viable alternative to tamoxifen for the treatment of advanced, metastatic breast cancer, as well as in the neoadjuvant and extended adjuvant settings. Here we describe the first efficacy and safety analysis of BIG 1-98, a large, randomized, independently conducted clinical trial designed specifically to assess and compare the efficacy of sequential or up-front use of letrozole and/or tamoxifen as adjuvant therapy for patients with early breast cancer. The analysis reported here combined the monotherapy arms of letrozole and tamoxifen with the truncated sequential arms. Patients randomized to letrozole had a 19% reduction in the risk of a disease-free survival event (hazard ratio 0.81; P=0.003), especially reducing distant metastases (hazard ratio 0.73; P=0.0012). These results establish letrozole as part of standard adjuvant therapy for postmenopausal women with endocrine-responsive breast cancer.     

Facilitating Breast-Conserving Surgery and Preventing Recurrence: Aromatase Inhibitors in the Neoadjuvant and Adjuvant Settings

Breast-conserving surgery (BCS) is an attractive option for many patients with early-stage breast cancer, because it provides a better cosmetic outcome than modified radical mastectomy, while reducing surgical morbidity. In patients with large, operable breast tumors who are ineligible for BCS, neoadjuvant therapy is a useful option for reducing the tumor size and for increasing the proportion of candidates for BCS. In patients with endocrine-responsive tumors, neoadjuvant endocrine therapy with either tamoxifen or an aromatase inhibitor (AI; anastrozole, letrozole, or exemestane) provides an alternative to neoadjuvant chemotherapy. Clinical trials have demonstrated the superiority of neoadjuvant AIs over tamoxifen in achieving a clinical response and increasing the frequency of BCS. In addition, adjuvant endocrine therapy with AIs, whether used as initial therapy instead of tamoxifen, in a switching strategy after 2–3 years of tamoxifen, or as extended adjuvant therapy after 5 years of adjuvant tamoxifen, has been shown in several randomized clinical trials to improve disease-free survival, reduce distant metastases and, in some cases, improve overall survival. The availability of the AIs for effective and well-tolerated neoadjuvant and/or adjuvant endocrine therapy represents an important advance in breast cancer treatment, and surgeons should be familiar with these new therapeutic options.     

Importance of correlative science in advancing hormonal therapy and a new clinical paradigm for neoadjuvant therapy

Improvement in endocrine therapy for estrogen receptor (ER)-positive breast cancer will require prevention or modulation of resistance, based on identification and targeting of the responsible molecular mechanisms. Our approach to this problem has been to focus on neoadjuvant endocrine treatment because that permits comparative evaluation of pretreatment tumor biopsies and surgical tumor specimens. We have begun utilizing this clinical paradigm by exploring semiquantitative changes in the expression of molecular markers within tumors treated with either tamoxifen or the aromatase inhibitor letrozole in a randomized trial. This investigation is beginning to elucidate the influence of growth factor pathways that interact with the ER, especially HER1 (epidermal growth factor receptor [EGFR]) and HER2. The results indicate that the distinct mechanisms by which tamoxifen and letrozole inhibit ER signaling may produce quite marked differences in clinical and biomarker outcomes in the subset of tumors that coexpress HER1 and/or HER2 with ER, favoring estrogen-deprivation therapy. Ongoing investigations are examining gene expression profile changes associated with neoadjuvant endocrine therapy, as well as inhibitors of growth factor signaling that may modulate tamoxifen resistance.     

Neoadjuvant endocrine therapy in breast cancer

The clinical benefits of endocrine therapy for patients with hormonosensitive breast cancer are well established. For many years, five years' treatment with tamoxifen was the gold standard of adjuvant treatment. The recent development of new endocrine agents provides physicians with the opportunity to take a more effective therapeutic approach. Nevertheless, the success of neoadjuvant endocrine therapy is much more recent and less frequently reported in the literature. This article reviews the studies published on neoadjuvant endocrine treatment (tamoxifen and aromatase inhibitors). According to the literature, neoadjuvant endocrine therapy seems to be effective and well tolerated. The newer generation of aromatase inhibitors (letrozole, anastrozole, exemestane) appear to result in better overall response rates and more conservative surgery than tamoxifen. Patients with an ER Allred score of 6 and over are most likely to respond and gain clinical benefit. The optimal duration of neoadjuvant therapy has not yet been investigated in detail. These preliminary results are interesting and should be confirmed by further studies.     

A roundtable discussion of aromatase inhibitors as therapy for breast cancer

This article summarizes the conclusions of a meeting of diverse breast cancer experts who discussed issues, controversies, and new clinical trial results relevant to the use of aromatase inhibitors for treating postmenopausal women with breast cancer. The new generation of aromatase inhibitors (anastrozole, letrozole, exemestane) have largely replaced megestrol acetate as a second-line therapy in postmenopausal women with hormone-responsive advanced breast cancer. In addition, anastrozole and letrozole have been shown to be superior to tamoxifen for first-line therapy. Finally, recent results suggest that anastrozole may be superior to tamoxifen as adjuvant therapy for early stage disease in postmenopausal women with hormone-responsive disease.     

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.     

Aromatase inhibitors--extending the benefits of adjuvant therapy beyond tamoxifen

Adjuvant tamoxifen is still considered standard care for postmenopausal women with early stage hormone receptor-positive breast cancer. However, efficacy and safety of tamoxifen are limited by its partially estrogenic properties. Aromatase inhibitors have proven highly effective in advanced breast cancer and are currently being investigated in the adjuvant setting, either as an alternative to or in sequence with tamoxifen, or as extended adjuvant therapy following tamoxifen. Results of several adjuvant aromatase inhibitor trials have been published and strongly indicate that efficacy may be increased compared with tamoxifen alone. This review will examine the published data, discuss ongoing trials, and address the question of how to best integrate the aromatase inhibitors into adjuvant treatment.     

Adjuvant and extended adjuvant use of aromatase inhibitors: reducing the risk of recurrence and distant metastasis

In patients with early-stage breast cancer, all recurrences are associated with an increased risk of mortality, especially distant metastases. Adjuvant tamoxifen therapy for 5 years is effective in postmenopausal patients for the prevention of disease recurrence but is associated with increased risk of rare, potentially fatal adverse events such as endometrial cancer, stroke, and pulmonary embolism. Recently, randomized clinical trials have shown aromatase inhibitor therapy to be superior to tamoxifen therapy for the prevention of disease recurrence. Switching to an aromatase inhibitor after 2-3 years of tamoxifen treatment has been shown to provide superior disease-free survival compared with completing 5 years of tamoxifen. Among approved aromatase inhibitors (letrozole, anastrozole, and exemestane), letrozole is the only one approved as extended adjuvant therapy after completing 5 years of tamoxifen. These results suggest that 10 years of adjuvant endocrine therapy is superior to 5 years of tamoxifen alone.     

Adjuvant endocrine therapy in postmenopausal breast cancer patients

Tamoxifen has been the endocrine agent of choice for adjuvant hormonal therapy for early breast cancer since approval in 1986. Five years of tamoxifen treatment produced a significant reduction in recurrence and death over more than 10 years of follow-up in women with estrogen receptor-positive (ER+) breast cancer. In large randomised trials, the standard of 5 years tamoxifen has been challenged by third-generation aromatase inhibitors (AIs) in the adjuvant setting. This review provides a synopsis of the most recent trial results and a discussion of remaining areas of uncertainties. Although currently tamoxifen still remains a valid option, increasing evidence from the new AI adjuvant trials suggests that optimised adjuvant endocrine treatment should incorporate an AI either as initial or as sequential therapy.     

Recommendations from an International Consensus Conference on the Current Status and Future of Neoadjuvant Systemic Therapy in Primary Breast Cancer

The use of neoadjuvant systemic therapy (NST) for the treatment of primary breast cancer has constantly increased, especially in trials of new therapeutic regimens. In the 1980 s, NST was shown to substantially improve breast-conserving surgery rates and was first typically used for patients with inoperable locally advanced or inflammatory breast cancer. Investigators have since also used NST as an in vivo test for chemosensitivity by assessing pathologic complete response. Today, by using pathologic response and other biomarkers as intermediate end points, results from trials of new regimens and therapies that use NST are aimed to precede and anticipate the results from larger adjuvant trials. In 2003, a panel of representatives from various breast cancer clinical research groups was first convened in Biedenkopf to formulate recommendations on the use of NST. The obtained consensus was updated in two subsequent meetings in 2004 and 2006. The most recent conference on recommendations on the use of NST took place in 2010 and forms the basis of this report.     

How to treat male breast cancer

The prevalence for breast cancer in males in Europe is estimated to be 1 or less per 100,000. Male breast cancer has a peak incidence at the age of 71 years. There are no randomized data giving information on the optimal therapy for male breast cancer patients, thereby limiting firmer conclusions. The preferred primary surgical therapy is modified radical/simple mastectomy, but breast-conserving surgery has also been used in males. Post-operative radiotherapy should be used on a more routine basis; as males have shorter breast-anatomical distances and males are diagnosed at a later stage compared with females. The so far preferred adjuvant therapy modality has been tamoxifen for patients with endocrine responsive disease. The use of aromatase inhibitors in males is more controversial, since they may not deplete the estradiol levels sufficiently. Different chemotherapy regimens have been used in the adjuvant and metastatic setting. The use of adjuvant therapy has in institutional and review comparisons been demonstrated to result in an improved outcome.     

Prescribing extended adjuvant letrozole

The efficacy of 5 years of adjuvant tamoxifen in preventing disease recurrence in patients with breast cancer has been well established. Once patients have completed tamoxifen therapy, however, recurrence risk remains but treatment options are limited. Aromatase inhibitors such as letrozole are emerging as potential alternatives to tamoxifen therapy and as an option after tamoxifen. The pioneering MA-17 trial was designed to evaluate the efficacy and safety of letrozole in the extended adjuvant setting in postmenopausal women who remained disease-free after about 5 years of tamoxifen. The trial was unblinded at first interim analysis after letrozole proved more effective than placebo in improving disease-free survival. As such, the optimal duration of extended adjuvant letrozole was left in question. However, recent results from cohort analysis in MA-17 have shown an ongoing and increasing benefit of letrozole for up to 4 years after tamoxifen, suggesting that longer periods of extended adjuvant letrozole are safe and clinically beneficial.     

The impact of adjuvant endocrine therapy on reducing the risk of distant metastases in hormone-responsive breast cancer

SUMMARY: The primary goal of systemic adjuvant therapy for breast cancer is to control the risk of recurrence following surgery, thereby improving long-term survival. For many years, tamoxifen has served as the standard adjuvant endocrine therapy for postmenopausal women with hormone-sensitive breast cancer. The entry of the third-generation aromatase inhibitors (AIs) exemestane, anastrozole and letrozole as adjuvant therapy has introduced several different treatment options. Indirect comparisons suggest that appreciable differences may exist between the AIs in terms of early risk reduction, especially the risk for early distant metastases. Possible differences in efficacy may be related to differences in potency. Two ongoing trials directly comparing two AIs - the Femara versus Anastrozole Clinical Evaluation and MA.27 - may provide further information.     

Tolerance of adjuvant letrozole outside of clinical trials

Recently aromatase inhibitors have become a standard care as an adjuvant treatment for many postmenopausal patients with hormone receptor positive early breast cancer. Adjuvant letrozole was made available either immediately postoperative, after 2-3years of tamoxifen, or as an extended treatment after 5years of tamoxifen. Between October 2003 and October 2005, we analyzed the subjective tolerance in 185 postoperative early breast cancer patients receiving letrozole outside of a clinical trial. The most prominent toxicity was musculoskeletal pain. In addition hot flushes, increased fatigue, nausea, vomiting, anorexia, mood disturbances, vaginal dryness, hair loss and rash were also recorded. In contrast to the prospective randomized clinical trials, a high drop-out rate of 20% was documented, mainly due to aromatase inhibitor-associated arthralgia syndrome interfering significantly with the daily life of our patients. Although adjuvant aromatase inhibitors have proven to be generally superior to tamoxifen in the adjuvant setting, it is important to focus attention on the tolerance during the adjuvant therapy and to balance this against the potential benefit in individual patients. Alternative options including switching to tamoxifen remain available.     

Postmenopausal advanced breast cancer: options for therapy after tamoxifen and aromatase inhibitors

All patients receiving endocrine treatment for advanced breast cancer (ABC) eventually progress, resulting in a need for new therapies that lack cross-resistance with existing agents. Oestrogen receptor (ER) modulators such as toremifene and raloxifene have poor efficacy following tamoxifen failure, whereas the non-steroidal aromatase inhibitors (AIs), anastrozole and letrozole and the steroidal AI exemestane are effective. Fulvestrant is a new ER antagonist with no agonist effects that is as effective as anastrozole in treating patients who have progressed on tamoxifen. AIs are replacing tamoxifen as first-line treatments for ABC and in the adjuvant setting, necessitating a re-evaluation of optimal sequencing. Preliminary data suggest that tamoxifen, exemestane and fulvestrant have activity in patients who have progressed on non-steroidal AIs and hence could be considered for use in this setting. Due to the apparent lack of cross-resistance between non-steroidal and steroidal AIs, non-steroidal AIs could also be effective following steroidal AI failure. Clinical trials are underway to assess the most appropriate treatment sequence following non-steroidal AI failure, with comparisons of fulvestrant and exemestane of major interest.     

Aromatase inhibitors in early breast-cancer treatment: The story so far

This paper describes the clinical evidence for using the aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, as adjuvant therapy for postmenopausal women with early breast cancer. Efficacy data for AIs are reviewed across different treatment strategies (initial, switched, sequenced or extended adjuvant therapy). Although trials are still ongoing, AIs have demonstrated superiority over tamoxifen in terms of disease-free survival and recurrence as initial therapy, and benefits in overall survival in switched or extended strategies. However, comparisons of efficacy data across trials are confounded by methodological differences between trials. To address this problem, mathematical models have been developed which allow for inter-trial comparisons. Results from these models indicate that initial adjuvant therapy with an AI is superior to initial therapy with tamoxifen, and suggest that initial AI therapy is better than starting tamoxifen and then switching to an AI. Further clinical trials are needed to ascertain the optimal length of treatment with an AI.     

Exemestane: a review of its clinical efficacy and safety

Aromatase inhibitors and inactivators are playing an increasing greater role in breast cancer treatment. Exemestane, a highly specific, steroidal aromatase inactivator, is the newest agent in this class. The drug is highly specific, and inhibits the in vivo conversion of androstenedione to oestrone (aromatization) by a mean of 97.9%. Exemestane has shown good efficacy and tolerability in multiple clinical trials among patients with metastatic breast cancer who have failed one or more previous hormonal therapies. Exemestane 25 mg/day slows disease progression and reduces tumour-related signs and symptoms and the drug exhibits a partial lack of cross-resistance with the non-steroidal aromatase inhibitors. Response rates to exemestane of 14% to 29% were observed including patients with visceral metastases, who have historically proven difficult to treat. In a large phase III trial, exemestane was found to be superior to megestrol acetate with respect to time to progression and overall survival. In addition, exemestane is currently under investigation as first-line therapy in metastatic disease and in sequence with tamoxifen in the adjuvant setting. Adverse events include low-grade hot flashes, nausea, and fatigue--mostly of mild to moderate intensity--and treatment-related discontinuations are rare. In conclusion, exemestane represents a novel and interesting drug for the treatment of advanced breast cancer, with exciting prospects for use in adjuvant therapy and, potentially, breast cancer prevention.