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Aromatase Inhibitors for Breast Cancer in Postmenopausal Women

Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

Correspondence: Susana M. Campos, M.D., M.P.H., Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA. Telephone: 617-632-6766; Fax: 617-632-5610; e-mail: Susana_Campos{at}dfci.harvard.edu

	ABSTRACT

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Third-generation aromatase inhibitors are potent inhibitors of the aromatase enzyme, which catalyzes the last step in estrogen biosynthesis. These agents are active against breast cancer in hormone-naïve postmenopausal women and in women who have experienced failure of tamoxifen or failure of tamoxifen plus other hormonal therapy. There are two types of aromatase inhibitors, irreversible steroidal activators (e.g., exemestane) and reversible nonsteroidal imidazole-based inhibitors (e.g., anastrozole, letrozole). Recent data suggest that some women who experience failure of one type of aromatase inhibitor can subsequently derive benefit from the other type. The reason for this lack of cross-resistance is unknown. This finding of non-cross-resistance between steroidal aromatase activators and nonsteroidal aromatase inhibitors offers the opportunity to increase the number of lines of hormone therapy before making the inevitable switch to more toxic chemotherapy, thus potentially improving quality of life for postmenopausal women with advanced disease.

Data from postmenopausal women with advanced disease suggest that steroidal and nonsteroidal aromatase inhibitors have similar tolerability profiles; however, emerging data suggest that there may be differences in their effects on end organs, which may become evident with longer term use, such as in the adjuvant or prevention settings. Steroidal agents appear to have beneficial effects on lipid and bone metabolism, whereas nonsteroidal agents may have neutral or unfavorable effects. These differences may be attributed to the androgenic effects of steroidal agents; clinical trials are currently under way to confirm these suspicions.

Key Words. Breast cancer • Aromatase inhibitor • Metastatic disease

	INTRODUCTION

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For more than 30 years, the antiestrogen tamoxifen has been the mainstay of hormonal therapy in postmenopausal women with breast cancer, followed by megestrol acetate and then the second-generation nonsteroidal aromatase inhibitor aminoglutethimide. Now, based on data from large, well-conducted clinical trials, aromatase inhibitors have replaced megestrol acetate for use after failure of tamoxifen [1–6] and are challenging tamoxifen as initial therapy in women with advanced disease [7–12]. Aromatase inhibitors also show promise for adjuvant therapy and neoadjuvant therapy, as well as in the prevention of breast cancer [13–16].

This article reviews data on the two types of aromatase inhibitors and their use in postmenopausal women with breast cancer.

	MECHANISM OF ACTION OF AROMATASE INHIBITORS

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Aromatase inhibitors can be categorized by generation and by mechanism of action. The third-generation aromatase inhibitors, which include exemestane, anastrozole, and letrozole, are potent and selective inhibitors of aromatase activity and are the focus of this review.

The aromatase enzyme is required for the last step in estrogen biosynthesis. The biochemical effect of aromatase inhibitors, as measured by the degree of aromatase inhibition, is approximately 98% for each of the third-generation agents [17–19]. This value also is reflective of the estrogen suppression achieved in the blood with these aromatase inhibitors.

There are two types of aromatase inhibitors, irreversible steroidal activators and reversible nonsteroidal imidazole-based inhibitors. Although both types interfere with the final step in estrogen biosynthesis, they do so by different mechanisms. Steroidal agents, such as exemestane, have an androgen structure and compete with the natural aromatase substrate androstenedione; they bind irreversibly to the catalytic site of aromatase causing loss of enzyme activity, and more aromatase enzyme must be produced before estrogen biosynthesis can resume. Therefore, steroidal agents are often referred to as suicide inhibitors. Because of their steroidal structure, exemestane and its 17-hydroexemestane metabolite have the potential for androgenic effects. The binding of exemestane to the androgen receptor is about 0.2% that of dihydrotestosterone [20], but the affinity of 17-hydroexemestane for the androgen receptor is about 100 times that of the parent compound [21].

Nonsteroidal imidazole-based agents reversibly interact with the cytochrome P450 moiety of the enzyme [22], and interference with estrogen biosynthesis is dependent on the continued presence of the nonsteroidal agent [23]. Nonsteroidal agents include the second-generation agent aminoglutethimide and the third-generation agents anastrozole and letrozole.

The in vitro effect of aromatase inhibitors on tissue aromatase activity in cultured fibroblasts has been used to demonstrate differences in the effects of steroidal and nonsteroidal agents on aromatase activity (Fig. 1). Differences in the mechanisms of action of steroidal and nonsteroidal aromatase inhibitors were evaluated by preincubating cultured fibroblasts from mammary adipose tissue with an aromatase inhibitor for 18 hours and then assaying the aromatase activity in the absence of the drug. Paradoxically, all the reversible nonsteroidal aromatase inhibitors caused enhanced aromatase activity at one or more concentrations tested. In contrast, exemestane and formestane (a second-generation steroidal agent) induced a marked inhibition of aromatase activity at all concentrations tested [3]. The clinical significance of these differences is currently unknown.

View larger version (17K): [in this window] [in a new window]   Figure 1. In vitro effect of aromatase inhibitors on tissue aromatase activity evaluated in cultured fibroblasts. The clinical significance of these differences is unknown. Reprinted with permission from Miller and Dixon [15].

	CLINICAL TRIALS DEMONSTRATING EFFICACY OF AROMATASE INHIBITORS IN POSTMENOPAUSAL WOMEN

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Advanced Disease

Aromatase Inhibitors after Failure of Tamoxifen
Initial research with aromatase inhibitors was conducted in postmenopausal women with advanced disease experiencing failure of tamoxifen. Each of the third-generation aromatase inhibitors was evaluated in this setting and each demonstrated efficacy (Table 1) [1–5]. Studies comparing aromatase inhibitors with megestrol acetate enrolled women whose disease became resistant to tamoxifen used either as adjuvant therapy or for advanced disease (Fig. 2). A substantial percentage of patients (approximately 40% in each study) received prior tamoxifen for adjuvant therapy only. Therefore, women enrolled in those trials were being treated either with initial hormonal therapy for advanced disease or after failure of tamoxifen for advanced disease.

View larger version (25K): [in this window] [in a new window]   Figure 2. Prior hormonal therapy in women enrolled in clinical trials comparing aromatase inhibitors with megestrol acetate. Approximately 40% of women enrolled in these trials received either an aromatase inhibitor or megestrol acetate as initial hormonal therapy for advanced disease and 60% received one of these agents after failure of tamoxifen for advanced disease.

The two studies comparing anastrozole efficacy with that of megestrol acetate did not report a statistically significant difference in key end points (OR, median survival, TTP, TTF) between anastrozole (1 mg daily) and megestrol acetate (160 mg daily), although results for each end point were numerically superior for anastrozole [2, 3]. In a subsequent pooled analysis of these two trials conducted at a median follow-up of 31 months, a statistically significant survival advantage was found for anastrozole [6]. As with the earlier individual analyses, the pooled analysis did not identify statistically significant differences in other end points. Both studies also evaluated 10 mg daily anastrozole and found no statistically significant differences between the 1-mg and 10-mg doses [2, 3]. In these studies, anastrozole and megestrol acetate were well tolerated; the most common adverse events reported in women taking anastrozole were asthenia, nausea, headache, hot flashes, and pain [24].

Two studies were also conducted with letrozole. One study, by Dombernowsky and colleagues [4], compared two doses of letrozole with megestrol acetate as second-line therapy in postmenopausal women. Letrozole, at a dose of 2.5 mg, produced a significantly higher overall OR rate (24%) than megestrol acetate (16%; p = 0.04) and than letrozole at a dose of 0.5 mg (13%; p = 0.004). The duration of OR was significantly longer for 2.5 mg letrozole than for megestrol acetate; 2.5 mg letrozole was significantly superior to megestrol acetate and 0.5 mg letrozole in TTF. For TTP, 2.5 mg letrozole was superior to the 0.5-mg dose but not to megestrol acetate. A significant dose effect on overall survival was observed with the higher letrozole dose, compared with the lower dose of letrozole. In contrast to the first study, the second study, by Buzdar and colleagues [5], showed no statistically significant differences among the three treatment groups for overall objective tumor response. Letrozole, 0.5 mg, was found to be superior to megestrol acetate in TTP and TTF. A dose-response relationship was not noted in the second study. Letrozole was well tolerated. The most frequent adverse events reported in women treated with letrozole were hot flashes, nausea, diarrhea, musculoskeletal pain, dyspnea, and headache [4, 5].

Direct comparative data on aromatase inhibitors are beginning to emerge. In an open-label, randomized, phase IIIB-IV study, anastrozole (1 mg daily) was compared with letrozole (2.5 mg daily) in 713 postmenopausal women with advanced breast cancer whose disease became resistant to tamoxifen used either as adjuvant therapy or for advanced disease [25]. Approximately half the patients had an unknown estrogen-receptor status. The primary end point, TTP, was similar in both groups, as were the secondary end points, including clinical benefit, TTF, duration of response, and duration of clinical benefit. In the overall population, the secondary end point OR rate statistically significantly favored letrozole (19.1% versus 12.3% for anastrozole, p = 0.014) [25]; however, this benefit was not seen in women with estrogen-receptor-positive disease (17.3% for letrozole versus 16.8% for anastrozole) [26]. Both agents were well tolerated, but nausea was more common with anastrozole (11%) than with letrozole (8%) [25].

In each of these comparative studies with megestrol acetate, the aromatase inhibitors offered a superior safety profile, with less weight gain and significant improvements in quality of life.

Aromatase Inhibitors versus Tamoxifen In comparative studies with tamoxifen, each of the third-generation aromatase inhibitors demonstrated clinical efficacy in postmenopausal women with advanced breast cancer (Table 2) [7–12, 27]. All the studies comparing aromatase inhibitors with tamoxifen enrolled postmenopausal women whose disease became resistant to tamoxifen as adjuvant therapy and women who were tamoxifen naïve (Fig. 3). None of the women in those studies had previously received tamoxifen for advanced disease. In fact, approximately 80% were tamoxifen naïve and had never even received tamoxifen for adjuvant therapy.

View larger version (27K): [in this window] [in a new window]   Figure 3. Prior hormonal therapy in women enrolled in clinical trials comparing aromatase inhibitors with tamoxifen. Approximately 80% of women treated for metastatic disease were tamoxifen naïve, while 20% had received tamoxifen for adjuvant therapy before progressing to advanced disease.

The steroidal agent exemestane was compared with tamoxifen in a randomized European Organization for Research and Treatment of Cancer (EORTC) phase II/III trial [7]. In the phase II portion of the study, exemestane produced an OR rate of 40.9% and a clinical benefit of 55.7%; the corresponding values for tamoxifen were 13.6% and 42.4%, respectively [7]. The positive results of this randomized phase II study led the EORTC to extend it to a randomized phase III study, which is still under way. The results of the phase III study are required to confirm these data.

Sequential Use of Aromatase Inhibitors There is evidence to suggest that aromatase inhibitors may maintain their efficacy when used sequentially. The steroidal aromatase inhibitor exemestane is effective after failure of tamoxifen and megestrol acetate [28] and after failure of tamoxifen and a nonsteroidal aromatase inhibitor (e.g., aminoglutethimide, anastrozole, letrozole) [29, 30]. The nonsteroidal aromatase inhibitors are effective after failure of exemestane [29, 30]. Clinical trials currently are being conducted to determine the most appropriate sequence for hormonal therapy administration.

Bertelli and colleagues evaluated the sequential use of steroidal and nonsteroidal aromatase inhibitors in postmenopausal women with advanced breast cancer [30]. Participants were permitted, but not required, to have had previous chemotherapy or tamoxifen either as adjuvant therapy or for advanced disease. This study is ongoing, but preliminary results are available. About 60% of participants had received previous endocrine therapy. Women receiving exemestane as their first aromatase inhibitor were administered anastrozole or letrozole at the time of disease progression, and women receiving letrozole or anastrozole as their first aromatase inhibitor were given exemestane at the time of disease progression. Women treated with exemestane as their first aromatase inhibitor achieved an OR rate of 18.7% and clinical benefit rate of 46.9%. OR rates and clinical benefit rates were 10% and 40%, respectively, in women receiving letrozole or anastrozole after experiencing failure of exemestane, and 4.2% and 25%, respectively, in women receiving exemestane after experiencing failure of anastrozole or letrozole [30]. Other clinical studies also suggest noncross-resistance between steroidal and nonsteroidal agents [29] and the effectiveness of aromatase inhibitors even after several lines of hormonal therapy (Table 3) [1–5, 7, 9–12, 28].

A pilot, randomized, open-label, crossover, multicenter study (by the Spanish Breast Cancer Research Group, GEICAM) [34] will assess the sequential use of exemestane followed by anastrozole at progression compared with the opposite sequence in 100 postmenopausal women with hormone-receptor-positive advanced breast cancer. The primary outcome measure will be response rate.

Collectively, these data demonstrate that aromatase inhibitors are effective treatment for advanced breast cancer in postmenopausal women, including hormone-naïve women and women who have experienced failure of tamoxifen, tamoxifen plus megestrol acetate, or multiple lines of hormonal therapy.

Adjuvant Therapy
The use of aromatase inhibitors for adjuvant therapy is a natural extension of their successful use in advanced disease. Research is being conducted with each of the aromatase inhibitors in this setting, but the first results to be released are from the Arimidex or Tamoxifen Alone or in Combination (ATAC) study enrolling 9,366 patients. Postmenopausal women with operable breast cancer were randomized to treatment with anastrozole (1 mg daily), tamoxifen (20 mg daily), or the combination for 5 years [13]. At a median follow-up of 47 months, there were no significant differences between the tamoxifen and the combination arms. However, anastrozole alone was superior to tamoxifen alone in disease-free survival (p = 0.03) and time to first recurrence (p = 0.015), with the benefits being most apparent in hormone-receptor-positive women. There also was a lower incidence of contralateral breast cancer in anastrozole-treated women versus tamoxifen-treated women (p = 0.06), which reached statistical significance in those who were hormone-receptor positive (p = 0.042) [35].

Long-term safety takes on added importance in this setting because adjuvant hormonal therapy is typically administered for several years to women who are likely to experience long-term survival. Safety data presented after 37 months of treatment in the ATAC study reveal that patients treated with anastrozole had lower rates of endometrial cancer (relative risk [RR] = 0.25), vaginal bleeding (RR = 0.54), vaginal discharge (RR = 0.25), cerebrovascular events (RR = 0.49), thromboembolic events (RR = 0.59), and hot flashes (RR = 0.87) than women receiving tamoxifen. Anastrozole-treated women had a higher incidence of musculoskeletal disorders (RR = 1.28) and more fractures (RR = 1.60). Although the percentage of women with adverse events was similar in both arms (92.1% for anastrozole versus 93.3% for tamoxifen), fewer women withdrew from the anastrozole arm (24.1% versus 28.3%), and significantly fewer withdrew due to adverse events (5.6% versus 8.1%) [13]. Similar long-term data are not yet available for the other aromatase inhibitors, but large, randomized, clinical trials are currently maturing (Table 4).

Although this article focuses on the use of aromatase inhibitors in postmenopausal women, it is important to mention that there are several trials using aromatase inhibitors (in the presence of ovarian function suppression) in the adjuvant setting in premenopausal women. One such trial is the Suppression of Ovarian Function Trial (SOFT). This is a phase III trial evaluating the role of ovarian function suppression and exemestane as adjuvant therapy in premenopausal women with endocrine-responsive breast cancer. The Tamoxifen and Exemestane Trial (TEXT) and Premenopausal Endocrine-Responsive Chemotherapy (PERCHE) trial also are evaluating the use of exemestane in premenopausal women [37, 38].

Breast Cancer Prevention
Epidemiologic studies have clearly demonstrated a link between estrogen exposure and breast cancer development [39]. As further evidence of this link, the antiestrogen tamoxifen has been shown to prevent the development of breast cancer in women with above average cancer risks [40]. However, the use of tamoxifen has been limited by an association with endometrial cancer, thromboembolic events, and tolerability concerns [41].

The same rationale for the use of tamoxifen in breast cancer prevention applies to the aromatase inhibitors. However, since there is evidence that both estrogens and estrogen metabolites may initiate breast cancer [42], aromatase inhibitors may offer added benefit. Whereas antiestrogens block the action of estrogens, leaving potentially carcinogenic estrogen metabolites available to exert their effects, aromatase inhibitors block the formation of estrogens and, therefore, estrogen metabolites.

Initial data supporting the use of tamoxifen for prevention were obtained from clinical trials demonstrating a lower incidence of contralateral breast cancer in tamoxifen-treated women. Likewise, early data from the ATAC trial demonstrate a greater reduction in the incidence of contralateral breast cancer with anastrozole than with tamoxifen, particularly in women with hormone-positive disease [13]. However, in contrast to tamoxifen, aromatase inhibitors have few tolerability concerns. Information about long-term effects is beginning to emerge from adjuvant therapy trials.

Several trials are currently under way to assess the role of aromatase inhibitors in breast cancer prevention (Table 5).

Neoadjuvant Therapy
The rationale for the use of aromatase inhibitors for neoadjuvant therapy is to shrink hormone-responsive tumors before surgical resection. Each of the aromatase inhibitors has been successfully evaluated in this setting; they are associated with dramatic reductions in aromatase activity in breast cancer tissue and in nonmalignant surrounding tissue and a substantial reduction in tumor volume, thus allowing the use of breast-conserving surgery [14, 16, 43, 44].

Aromatase Inhibitor Safety in Postmenopausal Women
Aromatase inhibitors are generally well tolerated, and adverse events are usually mild to moderate in postmenopausal women with metastatic disease. In comparative trials with megestrol acetate, fewer women treated with aromatase inhibitors discontinued treatment because of adverse events, and weight gain was less problematic. The most commonly reported adverse events in women treated with aromatase inhibitors were hot flashes, nausea, vomiting, headache, and fatigue [1–6].

The effects of chronic aromatase inhibitor administration are being assessed in adjuvant therapy and prevention trials and will be key factors in determining the usefulness of these agents in long-term therapy settings. Hot flashes, cardiovascular disease, and osteoporosis are important issues for postmenopausal women because they are at increased risk for these complications due to age-related loss of ovarian estrogen production. Since aromatase inhibitors are currently used primarily in postmenopausal women, there is considerable interest in how they affect the incidence of hot flashes and bone and lipid metabolism.

Hot Flashes
In a small phase II study comparing exemestane with tamoxifen for first-line hormone therapy of metastatic breast cancer in postmenopausal women, the incidence of grade 2 or greater hot flashes was lower with exemestane (3.2%) than with tamoxifen (13.5%) [7], while the incidences of hot flashes of any grade were 23.3% and 28.8%, respectively [45]. These results are being confirmed in the phase III portion of that study. When used for advanced disease, the incidence of hot flashes of all grades with nonsteroidal aromatase inhibitors was similar to that reported with tamoxifen [12, 27]. However, in the ATAC adjuvant therapy trial, the incidence of hot flashes was higher in the tamoxifen-treated group (40.3%) than in the group treated with anastrozole alone (35.0%) [46].

Lipid Metabolism
The effect of exemestane on lipid metabolism was evaluated in a subset of 122 (only 72 patients were included in the substudy) postmenopausal women with advanced breast cancer enrolled in a phase II/III study comparing exemestane with tamoxifen for first-line therapy [47]. After 24 weeks of treatment, there were no changes in total cholesterol, high-density lipoprotein cholesterol, or apolipoprotein A1/apolipoprotein B (Apo A1/B) levels in patients treated with exemestane. Among patients treated with exemestame, there were significantly (p = 0.012) fewer patients with >20% elevations in triglyceride levels relative to those patients treated with tamoxifen [47].

Lipid effects of exemestane were further characterized in a study conducted by Goss et al. in 10-month-old Sprague-Dawley female rats. In that preclinical study, exemestane protected against the adverse lipid effects induced by oophorectomy [48].

Dewar and colleagues [49] report no significant lipid changes in postmenopausal women treated with anastrozole for fewer than 20 months. Wojtacki et al. [50] studied both anastrozole (n = 27) and letrozole (n = 3) in postmenopausal women for a median of 32 weeks. Their preliminary results suggest that neither anastrozole nor letrozole affect lipid metabolism. Harper-Wynne and coworkers [51] reported no negative effects on lipid metabolism after 3 months of treatment with letrozole. In contrast, in a study conducted in 20 postmenopausal women treated with letrozole at a dose of 2.5 mg daily for 16 weeks, there were significant increases in total cholesterol, low-density lipoprotein cholesterol, and Apo B levels [52].

These data suggest that the steroidal aromatase inhibitor exemestane may have beneficial effects on lipid metabolism that are not exhibited by the nonsteroidal agents anastrozole and letrozole. These remain preliminary data and must be confirmed in long-term studies.

Bone Metabolism
The study by Goss et al., evaluating the effect of exemestane on lipid metabolism in Sprague-Dawley rats, also evaluated the effect of exemestane on bone metabolism [48]. Exemestane protected against the negative effects of oophorectomy on bone metabolism. In a second study of similar design, both exemestane and 17-hydroexemestane protected against the negative effects of oophorectomy on bone metabolism, while letrozole offered no benefit [53].

The effect of letrozole (2.5 mg daily for 3 months) on bone metabolism was studied in 29 healthy postmenopausal women using a marker of bone resorption. The marker increased significantly, suggesting a possible negative impact of letrozole on bone [51].

In the large adjuvant therapy ATAC trial, women treated with anastrozole alone had a 7.1% incidence of fractures compared with a 4.4% incidence in women treated with tamoxifen alone. Musculoskeletal disorders were also more common in anastrozole-treated women [46]. The greater fracture risk noted in the ATAC trial is cause for concern when considering the use of nonsteroidal aromatase inhibitors for long-term administration.

Preclinical data suggesting that the steroidal aromatase inhibitor exemestane has a beneficial effect on bone metabolism that is not seen with nonsteroidal agents must be confirmed in long-term clinical trials.

	CONCLUSIONS

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Aromatase inhibitors are supplanting tamoxifen as the most widely used hormonal agent in the treatment of breast cancer. They are highly effective in postmenopausal women with advanced breast cancer, including hormone-naïve women and women who experience failure of tamoxifen alone or tamoxifen plus other hormonal agents [1–5, 7–12]. Emerging data also demonstrate efficacy in postmenopausal women treated in the adjuvant [13] and neoadjuvant [14, 16, 43, 44] settings. It is postulated that similar results also will be obtained with aromatase inhibitors in the adjuvant therapy of premenopausal women with endocrine-responsive breast cancer undergoing ovarian suppression [36, 37]. In addition, aromatase inhibitors are being evaluated for prevention and in combination with chemotherapy and targeted therapies.

Clinical trials are currently under way to determine the comparative safety and efficacy of various aromatase inhibitors, as well as the most appropriate sequence of administration of hormonal therapy, including tamoxifen, serum estrogen receptor downregulators, steroidal aromatase inhibitors, and nonsteroidal aromatase inhibitors. Current data suggest that there is a lack of cross-resistance between steroidal and nonsteroidal agents. Lack of cross-resistance will allow for another hormonal therapy option before switching to chemotherapy in women with advanced breast cancer.

Data from short-term studies in metastatic disease demonstrate that aromatase inhibitors are better tolerated than megestrol acetate and tamoxifen. Preliminary data comparing anastrozole with tamoxifen in the adjuvant setting also support the superior tolerability of aromatase inhibitors. Preclinical and short-term clinical data suggest that this may not be a class effect; steroidal agents may have beneficial effects on bone and lipid metabolism while nonsteroidal agents may have neutral or detrimental effects. It is postulated that these beneficial effects of steroidal aromatase inhibitors may be a result of the androgenic action of exemestane and its 17-hydroexemestane metabolite. However, these data must be confirmed in long-term clinical trials.

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Top Abstract Introduction Mechanism of Action of... Clinical Trials Demonstrating... Conclusions References

 

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