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The role of aromatase inhibitors in the adjuvant treatment of breast carcinoma†
The M. D. Anderson Cancer Center evidence-based approach
Version of Record online: 18 AUG 2004
Copyright © 2004 American Cancer Society
Volume 101, Issue 7, pages 1482–1489, 1 October 2004
How to Cite
Morandi, P., Rouzier, R., Altundag, K., Buzdar, A. U., Theriault, R. L. and Hortobagyi, G. (2004), The role of aromatase inhibitors in the adjuvant treatment of breast carcinoma. Cancer, 101: 1482–1489. doi: 10.1002/cncr.20522
The following faculty members participated in the development of this article: Banu Arun, M.D.; Daniel Booser, M.D.; Massimo Cristofanilli, M.D.; Francisco J. Esteva, M.D., Ph.D.; Ana M. Gonzalez-Angulo, M.D.; Sharon Giordano, M.D.; Marjorie Green, M.D.; Karin Gwyn, M.D.; Nuhad Ibrahim, M.D.; James L. Murray, M.D.; Lajos Pusztai, M.D., Ph.D.; Edgardo Rivera, M.D.; Eva Thomas, M.D.; Vicente Valero, M.D.; Ronald Walters, M.D. (Department of Breast Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas); Robert Bast, M.D. (Department of Gynecologic Oncology, University of Texas M. D. Anderson Cancer Center, Houston Texas); Therese Bevers, M.D.; Abenaa Brewster, M.D. (Department of Cancer Prevention, University of Texas M. D. Anderson Cancer Center, Houston, Texas); Thomas Buchholz, M.D.; Marsha McNeese, M.D.; Eric Strom, M.D. (Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas).
- Issue online: 17 SEP 2004
- Version of Record online: 18 AUG 2004
- Manuscript Revised: 15 JUN 2004
- Manuscript Accepted: 15 JUN 2004
- Manuscript Received: 11 MAY 2004
- aromatase inhibitors;
- adjuvant therapy;
- hormone receptor–positive;
- breast carcinoma
The authors examined the published evidence on the use of aromatase inhibitors (AIs) in the adjuvant setting in postmenopausal, hormone receptor–positive patients, and they provide recommendations for clinical management in 3 different situations: newly diagnosed women, women who have already received tamoxifen for 2–3 years, and women who have completed 5-years of tamoxifen and are disease free.
All double-blind, randomized, prospective studies were reviewed. Data sources included the MEDLINE data base, reviews, editorials, and experts.
The Arimidex, Tamoxifen Alone or in Combination (ATAC) trial, the Intergroup Exemestane Study (IES), and the MA-17 trial confirmed the superiority of AIs over tamoxifen in women with early-stage breast carcinoma, improving disease-free survival (DFS) considerably. In the ATAC trial, the 4-year DFS rate was 86.9% on anastrozole and 84.5% on tamoxifen (P = 0.03); in the IES, the 3-year DFS rate was 91.5% on exemestane and 86.8% on tamoxifen (P = 0.00005); and, in MA-17, the 4-year estimated DFS rate was 93% on letrozole and 87% on placebo (P ≤ 0.001). All studies were limited because of the immaturity of data, particularly concerning long-term safety. A negative impact on bone health was observed in all three trials. However short-term side effects were acceptable. In addition, the studies demonstrated a significant reduction in the frequency of new primary tumors in the contralateral breast.
Current data support anastrozole as first-line adjuvant hormonal therapy, or a change to AIs after 2–3 years of tamoxifen, or the use of letrozole at the end of a 5-year course of tamoxifen as first-choice treatment options for the management of hormone receptor–positive breast carcinoma in postmenopausal women. Ongoing clinical trials should help to define the precise timing, duration, and sequencing of AI therapy, in addition to the long-term tolerability profile and potential differences between anastrozole, letrozole, and exemestane. Cancer 2004. © 2004 American Cancer Society.
Historically, the selective estrogen receptor (ER) modulator (SERM) tamoxifen has been the gold standard for treatment of breast carcinoma in women with ER-positive disease. Tamoxifen is beneficial in adjuvant treatment irrespective of age, menopausal status, or use of chemotherapy.
Available data indicate that 5 years of tamoxifen is the standard course, because longer adjuvant therapy does not increase benefit, benefit may be reduced with a longer treatment course, and the incidence of serious adverse events increases.1 The odds of disease recurrence and death from disease in patients with breast carcinoma are reduced by 47% and 26%, respectively with 5 years of tamoxifen therapy. The reduction in annual hazard of disease recurrence (≈ 13%) continues for up to 15 years. Mortality related to breast disease also is reduced and ranges from 4% to 9% at 15 years of follow-up.2
However, tamoxifen's partial estrogen agonist effects, although they may be beneficial in preventing bone demineralization in postmenopausal women and in improving lipid profiles,3 are associated with an increased risk of endometrial carcinoma (2.5 fold) and thromboembolic disease (≈ 2.0-fold).4 Resistance to tamoxifen therapy in patients with early-stage breast carcinoma may occur as early as 12–18 months after the initiation of therapy; and, in some patients with resistant disease, tamoxifen can act as a stimulant of breast carcinoma cell growth.5 These observations and the fact that ≈ 10–20% of patients with ER-positive breast carcinoma who are treated with tamoxifen develop recurrent disease and die of metastatic disease within 5 years after their initial diagnosis have prompted the search for and development of new antitumor agents with different mechanisms of action and fewer adverse effects. Aromatase inhibitors (AIs) act by blocking the synthesis of estrogen in nonovarian tissue by inhibiting the cytochrome P450 enzyme aromatase. This enzyme catalyzes the conversion of androgens to estrogens in peripheral tissues (fat, muscle, etc.) and locally within established tumors. By inhibiting aromatase, the levels of estrogens are reduced by > 97% in postmenopausal women.6 Unlike tamoxifen, AIs lack any partial estrogenic agonist activity. Type 1 AIs are steroidal analogues of androstenedione and are known commonly as suicidal, noncompetitive inhibitors or enzyme inactivators. Type 1 AIs bind irreversibly, causing permanent inactivation of the enzyme complex until new enzyme is synthesized by peripheral tissues and/or tumor tissues. Type 2 inhibitors are nonsteroidal drugs and bind reversibly to the aromatase enzyme complex.
MATERIALS AND METHODS
Two nonsteroidal, third-generation AIs (anastrozole and letrozole) and one steroidal AI (exemestane) are available for clinical use. It has been shown that these three AIs are equivalent or superior to megestrol acetate as second-line therapy for metastatic breast carcinoma and to tamoxifen as first-line therapy for metastatic disease.7–14 In primary breast carcinoma neoadjuvant trials, AIs have been associated with higher clinical and radiologic response rates compared with tamoxifen, resulting in a greater frequency of breast-conserving surgery.15–18 This class of drugs is under evaluation as adjuvant therapy for primary breast carcinoma. Recently, the results of three international, multicenter, randomized trials evaluating the role of AIs in the adjuvant setting in postmenopausal patients have been published. Key features of those studies are summarized in Table 1.19–21 The trials included between 3000 and 9000 patients each; and, although their designs were completely different, they all demonstrated a clinical benefit in favor of AIs in terms of disease-free survival (DFS) and acceptable short-term safety. The presentation of these data can affect clinical oncology practice in academic and community centers. The American Society of Clinical Oncology Technology Assessment Working Group (the Working Group) stated in 200222 and confirmed in 200323 that the results from the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial, although they were very promising, were insufficient to change standard practice because of the lack of survival data and the relatively immature follow-up on which to base an analysis for safety and tolerability. The Working Group's recommendation was that anastrozole can be administered for postmenopausal patients in whom tamoxifen is contraindicated or not tolerated but that tamoxifen continued to be the standard of care. Similar guidelines were adopted at the International Breast Cancer Study Group Symposium in Europe at St. Gallen in 2003.24 However, the National Comprehensive Cancer Network has included AIs as a valid and acceptable option in the adjuvant setting for postmenopausal patients.25
|Interval between initial treatment and AI administration||Adjuvant||2–3 yrs of DFS while receiving tamoxifen||5 yrs of DFS while receiving tamoxifen|
|No. of patients||9366||4742||5187|
|Treatment arms||Anastrozole, 1 mg; tamoxifen, 20 mg; combination||Exemestane, 25 mg; tamoxifen, 20 mg or 30 mg||Letrozole, 2.5 mg; placebo|
|Planned treatment duration (yrs)||5||5||5 or 10|
|ER status lacking (%)||8||17||< 1|
|Secondary endpoint||Time to recurrence, incidence of contralateral breast tumors, distant recurrence, and OS||Long-term tolerability, incidence of contralateral breast tumors, and OS||Quality of life, long-term safety, and OS|
|Median follow-up (mos)||47||30||28|
|Key results||4 yr DFS: 86.9% in anastrozole arm, 84.5% in tamoxifen arm (P = 0.03)||3 yr DFS: 91.5% in exemestane arm, 86.8% in tamoxifen arm (P = 0.00005)||4 yr estimated DFS: 93% in letrotrozole arm, 87% in placebo arm (P ≤ 0.001)|
|Current trial status||Accrual completed; patients will receive their assigned treatment||Accrual completed; patients will be offered opportunity to switch to exemestane||Closed: all patients currently receive letrozole|
The impact of the three AI trials on the clinical management of patients with breast carcinoma remains to be defined; however, clinicians are obligated to inform patients about new and effective treatment options in three different situations for postmenopausal, hormone receptor–positive, early-stage breast carcinoma. These are 1) newly diagnosed, postmenopausal women with hormone receptor–positive disease; 2) postmenopausal women with hormone receptor–positive disease who already have received tamoxifen for 2 or 3 years; and 3) postmenopausal women with hormone receptor–positive disease who have completed 5 years of tamoxifen and are disease free.
Public domain literature was reviewed and discussed between the panel members. The objective of our group was to review the published evidence for each of these clinical situations and to provide recommendations for clinical management in these subsets of patients.
Newly diagnosed, postmenopausal women with hormone receptor–positive disease
At the time of this report, the only available data were based on the ATAC trial, which is the largest, single, adjuvant cancer treatment trial conducted to date and was designed as an international, randomized, double-blind, multicenter study for postmenopausal patients with histologically confirmed, invasive, operable breast carcinoma who had completed primary therapy (surgery with or without radiotherapy and with or without chemotherapy) and were candidates for adjuvant hormone treatment. Primary study endpoints were DFS and safety and tolerability. DFS was defined as the time from protocol registration to the earliest occurrence of local or distant recurrence, new primary breast carcinoma, or death from any cause. Patients were randomized in a 1:1:1 ratio across the 3 arms of the trial: 1) oral anastrozole 1 mg per day plus tamoxifen placebo, 2) oral tamoxifen 20 mg per day plus anastrozole placebo, or 3) oral anastrozole 1 mg per day plus oral tamoxifen 20 mg per day. After a median follow-up of 47 months, it was observed that anastrozole was more effective than tamoxifen, as determined by the primary study endpoint, DFS (hazard ratio [HR], 0.86; P = 0.03) (Table 1).19 In addition, several important tolerability benefits were noted (Table 2). Combination treatment was equivalent to tamoxifen and offered no efficacy or safety advantage over anastrozole alone. This arm of the study was stopped after the first analysis at a median of 33 months of follow-up. In preclinical models, concomitant administration of letrozole with tamoxifen at clinically recommended doses decreased the mean plasma level of letrozole by 37.6%.26 These observations were confirmed with the anastrozole/tamoxifen combination in the ATAC trial, with a 27% reduction in anastrozole plasma levels but without affecting the ability of AIs to suppress estradiol production. Based on the observed drug-to-drug interaction and the lack of clinical data demonstrating a clear advantage of the combination treatment arm, this combination was discontinued. Another possible explanation for the lack of benefit of the combination treatment is related to the estrogen agonist effect of tamoxifen becoming more evident after nearly complete estrogen suppression by the AI.26
|Event||Treatment arm (% of patients)|
|Discontinuation of treatment due to adverse events||11.1||7.8||12.6||15.4||3.6||4.5|
In the updated intention-to-treat analysis, which focused only on the anastrozole-alone arm and the tamoxifen-alone arm, the time-to-first-event curves continued to diverge. The absolute difference between treatments in the time to first event (defined as recurrences, new contralateral tumors, or death from any cause) was 1.5% at 37 months of follow-up and 2.4% at 47 months of follow-up, respectively, for the entire population. Similar results were observed in the ER-positive patients. At 3 years and 4 years of follow-up, the absolute differences in time to first event and time to recurrence increased over time, with proportional hazard reductions of 17% and 22% respectively, for anastrozole therapy versus tamoxifen therapy.
In an unplanned, retrospective, subgroup analysis presented at the San Antonio Breast Cancer Symposium in December, 2003, a greater difference in DFS in favor of anastrozole (HR, 0.48; range, 0.33–0.71) was seen in the ER-positive, progesterone receptor (PgR)-negative patient subgroup, which accounted for 19% of the total study population.27 PgR expression is regulated by estrogen and is considered a marker of ER-mediated transcription. PgR is expressed in very few ER-negative tumors. The precise prognostic role of PgR has not been defined firmly.2, 28 These data may be useful in the selection of adjuvant therapy on a biologic basis; however, they need to be confirmed in a prospective trial.
Postmenopausal women already on tamoxifen for 2–3 years
The IES group conducted a double-blind, randomized trial for hormone receptor–positive, postmenopausal women to evaluate whether, after 2–3 years of tamoxifen therapy, switching to exemestane was more effective than continuing tamoxifen therapy for the remainder of the 5 years of treatment.20 The primary endpoint was DFS, which was defined by the time of randomization to recurrence of breast carcinoma at any site, diagnosis of a second primary breast carcinoma, or death from any cause. Four thousand seven hundred forty-two patients were enrolled. Hormone receptor status was unknown in 17% of patients. After a median follow-up of 30.6 months, the HR for the exemestane group, compared with the tamoxifen group, was 0.68, indicating a 32% reduction in risk. The absolute benefit in terms of DFS was 4.7% (95% confidence interval, 2.6—6.8) at 3 years after randomization on study.20 Overall survival did not differ significantly between in the two groups. Ninety-three deaths occurred in the exemestane group, and 106 deaths occurred in the tamoxifen group. Severe toxic effects of exemestane were rare. In particular, no weight gain, acne, or hypertrichosis were noted during long-term administration, as reported previously in the treatment of patients with advanced disease.29 According to an unplanned subgroup analysis, exemestane seemed to be equally effective in both PgR-positive and PgR-negative subsets, contrary to the ATAC trial findings.20, 27
Another small, prospective trial evaluated the role of anastrozole after 2–3 years of tamoxifen in a randomized study. The data were presented at the San Antonio Breast Cancer Symposium in 2003 and are available only in abstract form. A similar benefit in terms of DFS was reported on a cohort of 426 patients with lymph node-positive, ER-positive breast carcinoma who were randomized either to continue tamoxifen for 5 years or to change to anastrozole after ≥ 2 years of tamoxifen.30 The HR of recurrence for the women who switched to anastrozole was 0.36 (95% confidence interval, 0.17–0.75; P = 0.006), and the HR for death was 0.18 (95% confidence interval, 0.02–1.57; P = 0.07). Serious adverse events were more common in the women who continued on tamoxifen (29 events vs. 14 events).
Postmenopausal women who completed 5 years of tamoxifen and remained disease free
The MA-17 adjuvant study compared 5 years of letrozole versus placebo after the completion of 5 years of adjuvant tamoxifen in hormone receptor–positive, postmenopausal women.21 The study was discontinued after the first interim analysis at a median of 2.4 years of follow-up because of a highly significant reduction in breast carcinoma recurrences in the letrozole-treated group. The HR for local and distant recurrences or for new contralateral breast carcinomas in the letrozole group, compared with the placebo group, was 0.57 (95% confidence interval, 0.43–0.75; P = 0.00008). This translated into an absolute difference of 2.2% in the rate of breast carcinoma events, including distant metastases, ipsilateral recurrences, and contralateral breast carcinomas. No significant difference in overall survival was observed.21 On the basis of these favorable data and the acceptable toxicity profile of letrozole after short-term administration, the data-monitoring committee, according to established interim analysis criteria, recommended an early data release. Although a relative reduction in the hazard of death from any cause reportedly was 24% for the letrozole group, this result was not statistically significant (95% confidence interval, 0.48–1.21; P = 0.25). It is possible that a survival benefit will never be confirmed due to the early termination of the trial. Due to the short follow-up, concerns remain about possible long-term adverse effects of estrogen deprivation over the cardiovascular system as well as an increased risk of osteoporosis. The early data release left unanswered the question of optimal treatment duration.
Safety and Tolerability
Differences in the safety profile between tamoxifen and the AIs are substantial and may be the major determinants in switching to AI therapy. Several differences among the third-generation AIs have been reported in terms of selectivity for the aromatase enzyme, pharmacokinetics, lipid profile, bone reabsorption, and steroidogenesis. These effects may become apparent only after long-term dosing.29 The treatment compliance with the use of AIs, as reported in Table 2, was better than tamoxifen in the ATAC trial and was similar to tamoxifen in the IES trial: Both were double-blind trials.
Anastrozole was associated with significantly fewer patient withdrawals from treatment than tamoxifen (21.9% vs. 26.0%; P = 0.0002) including fewer withdrawals due to drug-related adverse events (5.1% vs. 7.2%).19 In the IES trial, the randomly assigned treatment was stopped in 14.1% of the entire population in the study, including 12.6% of patients in the tamoxifen arm versus 15.4% of patients in the exemestane arm. In that trial, 5.0% of the tamoxifen group versus 5.8% of the exemestane group discontinued study drug because of adverse events.20 Women who were treated with either anastrozole or exemestane experienced fewer endometrial carcinomas, less vaginal bleeding and discharge, fewer venous thromboembolic events, fewer hot flushes, and fewer ischemic cerebrovascular events. The anastrozole and exemestane groups had greater numbers of patients with musculoskeletal disorders and bone fractures.19, 20 Increased rates of diarrhea and visual disturbances were seen with exemestane. In the MA-17 trial, hot flashes, arthritis, arthralgia, and myalgia were more frequent in the letrozole group, whereas vaginal bleeding was less frequent. There were new diagnoses of osteoporosis in 5.8% of women in the letrozole group and in 4.5% of women in the placebo group (P = 0.07); the rates of fracture were similar but were higher numerically in the letrozole group.
Any direct comparison among the three trials concerning safety and compliance is not possible, because the criteria used to monitor adverse events and timing of the introduction of AIs were different. Moreover, differences in protocol definitions of adverse effects, at least for cardiovascular events, may account for the variability observed in the trials: In the ATAC trial, in which only ischemic cardiovascular disease was considered, the reported incidence was 2.5% for anastrozole compared with 1.9% for tamoxifen. Similarly, there was no significant increase in the incidence of myocardial infarction observed in the IES trial (1.0% in the exemestane group vs. 0.4% in the tamoxifen group). Conversely, the incidence of cardiovascular events other than myocardial infarction was greater in the IES study in both treatment groups, but the cardiovascular criteria were not defined clearly in the published Methods section of the report.
Recent studies have shown that all third-generation AIs are associated with increased bone reabsorption, whereas it is known that tamoxifen provides some protection against osteoporosis and bone fractures because of its partial estrogenic agonist effect.31, 32
The ATAC, MA-17, and IES trials confirmed that AIs have an impact on the frequency of osteoporosis diagnoses and on the reported number of fractures. Fractures may be the result of a dual effect, i.e., the loss of the protective estrogen agonist effect of tamoxifen and estrogen deprivation caused by AIs. Nonetheless, in an updated safety analysis of the ATAC trial, the encouraging safety profile of anastrozole versus tamoxifen was maintained, particularly regarding the risk of fracture. There has not been an increase in hip fractures over time.19
The ATAC, IES and MA-17 trials are the largest randomized studies completed to date, with the largest number of postmenopausal patients with hormone receptor–positive, primary breast carcinoma included in therapeutic trials in the history of breast carcinoma treatment. Although each has a different design, these trials, as summarized in Table 1, provide evidence that AIs are more effective than tamoxifen in preventing local and distant disease recurrences and preventing new, primary, contralateral breast carcinomas in postmenopausal patients in 3 specific situations: in the adjuvant endocrine setting only as endocrine intervention, in patients who have received 2–3 years of tamoxifen, and in patients who have completed 5 years of tamoxifen.
The data from these three trials cannot be compared between trials, because the differences in timing for the start of the AIs introduce a selection bias of the hormone-sensitive population in the IES and MA-17 studies. Because many of the hormone-resistant recurrences are detected during the first 2–5 years after diagnosis, the newly diagnosed patient group that participated in the ATAC trial is quite different from the IES group, because those patients who developed recurrent or metastatic disease during the 2–3 years of tamoxifen were excluded from consideration; this is even more of a selection factor for the MA-17 study. In other words, in the ATAC trial, all ER-positive patients were included, whether they were hormone-sensitive or hormone-resistant; whereas, in the IES and MA-17 trials, only the best candidates for hormone therapy, namely, the hormone-sensitive patients, were included.
The strengths of the ATAC, IES, and MA-17 studies are their statistical power, their efficacy analysis according to the intention-to-treat principle, and their double-blind treatment comparison. The absolute reduction in recurrence-free survival for adjuvant AIs over tamoxifen, even if it is modest, is maintained over time in the ATAC trial. A significant reduction in the frequency of new primary tumors in the contralateral breast was a common finding across all three AI trials.
One of the weaknesses of these 3 trials is the immaturity of data, particularly concerning long-term safety, with a median follow-up of 47 months for the ATAC trial,33 30.6 months for the IES,20 and 28 months for the MA-17 study.21 In particular the MA-17 trial, although it was stopped according to preestablished statistical rules, leaves the questions of optimal treatment duration undefined and the question of long-term toxicity undocumented.
The ATAC, the MA-17, and IES trials confirmed that AIs have a negative impact on bone. Newer trials have been designed to assess whether the use of bisphosphonates may prevent osteoporosis and fractures in patients who are treated with AIs. Although endocrine therapies can affect bone mineral density loss, the bone mineral density of women on treatments that reduce estrogen levels can be monitored, and preemptive treatment can be given to reduce the therapy-related fracture risk. All patients on adjuvant AI therapy should receive vitamin D and calcium supplements and should be encouraged to maintain weight-bearing exercise, and patients who have evidence of bone loss at baseline also should receive an oral bisphosphonate. It is recommended that patients be evaluated and monitored according to established guidelines.34
All three trials have shown a better DFS, but none have demonstrated a better overall survival with AI treatment. Longer follow-up and additional safety data are needed to confirm results of the interim analyses and to confirm further the benefits of long-term use of AIs. Even if previous experience of early reports of DFS improvement in adjuvant therapy for breast carcinoma did translate into an overall survival benefit,35 it has been argued that the short follow-up may obscure the efficacy of a full 5 years of tamoxifen as well as its carry-over effect, thus precluding a meaningful analysis of both long-term efficacy and toxicity of adjuvant AIs.
At least for the ATAC trial, even in the unlikely scenario of no carry-over effect of the anastrozole benefit in Years 5–9, the 22% benefit seen in patients with receptor-positive disease in Years 0–4 is large enough to balance the carry-over benefit of tamoxifen compared with placebo in Years 5–9. Thus, after 10 years of follow-up, anastrozole is unlikely to be less efficacious than tamoxifen, provided it retains a more favorable safety profile.36
A risk-adapted strategy could be outlined using AIs only for patients at high risk of disease recurrence and treating low-risk patients with tamoxifen.37 However, in the published trials, solid evidence supporting the hypothesis that only high-risk patients can benefit from AIs is lacking.
In the ATAC study, standard prognostic factors predicted recurrence, as expected; and the beneficial effect of anastrozole over tamoxifen with respect to time to recurrence was evident in all subgroups, with the exception of hormone receptor–negative or chemotherapy-treated patients. In an unplanned subgroup analysis in the MA-17 trial, the effect of letrozole was similar in patients with lymph node-negative disease and patients with lymph node-positive disease (HR for recurrence or contralateral breast carcinoma, 0.47; P = 0.005 vs. 0.60; P = 0.003).
Unfortunately in the IES published results, grade and tumor size were not reported. However, for lymph node status, exemestane appeared to be equally effective in both lymph node positive and node negative disease.20
There are remaining issues that have not been answered by the reported adjuvant AI trials: optimal duration of treatment with AIs; optimal use of tamoxifen with AIs; differences in terms of toxicity and long-term, end-organ effects of AIs; and whether AIs should be used concomitantly or sequentially with chemotherapy. Research related to aromatase inhibition resistance as well as the possible use of genomics-based and/or proteomics-based approaches for the selection of patients most likely to benefit from AI therapy is needed.
In postmenopausal women with hormone receptor–positive disease, it has been demonstrated that AIs are superior to other endocrine therapy as first-line therapy for tamoxifen-resistant, advanced breast carcinoma7–14 and as preoperative therapy in treatment-naive patients.15–18 The ATAC, IES, and MA-17 trials provide additional data confirming the superiority of AIs over tamoxifen in the treatment of early-stage breast carcinoma. The ATAC trial is the only trial to date that has reported 4 years of follow-up data on efficacy events.
Currently, a 5-year course of adjuvant tamoxifen remains a valid option for postmenopausal women with hormone receptor–positive breast carcinoma. However, adjuvant AIs can be offered to postmenopausal women with hormone receptor–positive breast carcinoma not only if there are contraindications to tamoxifen but also after a comprehensive discussion of the benefits and risks of AIs.
AIs offer improved efficacy over tamoxifen in a variety of adjuvant settings, and they offer the potential for preventing breast carcinoma with an acceptable safety profile. Although longer follow-up will allow further evaluation of long-term clinical effects of AIs, in view of the available data, the third-generation AIs represent an important clinical advance for postmenopausal women with early-stage breast carcinoma. AIs should be considered as the preferred adjuvant endocrine intervention, because they prevent recurrences, and patients with recurrent breast carcinoma seldom are cured. Therefore, despite several outstanding questions about long-term safety and their optimal use, AIs should be the first choice of endocrine therapy in the situations discussed (see Table 3). Ongoing clinical trials should help to define the precise timing, duration, and sequencing of AI therapy, in addition to the long-term tolerability profile and potential differences between anastrozole, letrozole, and exemestane.
|Newly diagnosed tumor||Anastrozole, tamoxifen||Anastrozole decreases the risk of disease recurrence and has a more favorable safety profile|
|After 2–3 yrs of tamoxifen use||Continue tamoxifen use for a total of 5 yrs; switch to AI to complete 5 yrs of treatment||AIs decrease the risk of disease recurrence|
|After completion of 5 yrs of tamoxifen use||No further therapy, letrozole||Letrozole decreases the risk of disease recurrence; optimal duration of treatment remains to be defined|
- 7Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature Phase III trials. Arimidex Study Group. Cancer. 1998; 83: 1142–1152., , , et al.
- 13Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol. 2003; 21: 2101–2109., , , et al.
- 16Comparison of anastrozole vs tamoxifen alone and in combination as neoadjuvant treatment of estrogen receptor-positive (ER+) operable breast cancer in postmenopausal women: the IMPACT trial [abstract 1]. Breast Cancer Res Treat. 2003; 82(Suppl 1): S6., , et al.
- 17Phase II study to define safety and efficacy of exemestane as preoperative therapy for postmenopausal patients with primary breast cancer—final results of the German Neoadjuvant Aromasin Initiative (GENARI) [abstract 239]. Breast Cancer Res Treat. 2003; 82(Suppl. 1):S55., , , .
- 25National Comprehensive Cancer Network. NCCN practice guidelines in oncology: breast cancer. Version 1.2006 [monograph online]. Available from URL: http://www.nccn.org/physician_gls/f_guidelines.html [accessed August 2, 2004].
- 27ATAC Trialists' Group. Analysis of time to recurrence in the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial according to estrogen receptor and progesterone receptor status [abstract 4]. Breast Cancer Res Treat. 2003; 82(Suppl. 1): S7., on behalf of the
- 30Anastrozole appears to be superior to tamoxifen in women already receiving adjuvant tamoxifen treatment [abstract 3]. Breast Cancer Res Treat. 2003; 82(Suppl. 1): S6–S7., , , et al.
- 33Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer. 2003; 98: 1802–1810., , , et al.