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Abstract

This article summarizes the current data regarding the use of the aromatase inhibitors as adjuvant hormonal therapy for postmenopausal women with early stage breast cancer. The article focuses on the five major trials examining the use of these drugs and their toxicity in the adjuvant setting. The data currently available suggest that the aromatase inhibitors are efficacious, either as upfront therapy or after a course of tamoxifen. Ongoing trials will compare these approaches and guide the use of these agents in the years to come.

Keywords

aromatase inhibitor breast cancer hormone receptor tamoxifen

Adjuvant hormonal therapy for postmenopausal women with hormone receptor-positive breast cancer has become far more complex over the last several years. Tamoxifen has been used in this setting for many years. It functions as a partial estrogen receptor (ER) antagonist, binding to the receptor and preventing downstream signaling. Almost two decades ago, the Scottish tamoxifen trial demonstrated an increase in both disease-free survival (DFS) and overall survival (OS) in women with ER-positive tumors treated with tamoxifen [1]. This benefit was observed in both node-positive and -negative patients, and was not dependent on menopausal status. The National Surgical Adjuvant Breast and Bowel Program (NSABP) B-14 trial also demonstrated an increase in DFS and OS in node-negative patients treated with 5 years of adjuvant tamoxifen after resection of an ER-positive breast cancer [2]. Based on the results of these trials and the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis, tamoxifen became the standard treatment for women with early stage, ER-positive breast cancer in the late 1980s [3].

Despite the clear benefits associated with adjuvant tamoxifen, many women still develop a recurrence of their disease. Moreover, for a minority of patients, the use of tamoxifen has been limited by the increased risk of endometrial cancer and venous clotting associated with the drug. New drugs have therefore been developed, which target the estrogen dependence of breast cancer through other mechanisms. The aromatase inhibitors (AIs) were developed to target estrogen dependence by preventing the peripheral conversion of adrenal androgens to estrogen through inhibition of the aromatase enzyme complex. These medications are useful only in postmenopausal women, who derive the majority of their estrogen from peripheral conversion of adrenal androgens. In premenopausal women, the use of AIs leads to increased ovarian aromatase activity, resulting in an increase in estrogen levels [4].

Amnioglutethimide was the first AI to be developed, but its use was limited by its concomitant suppression of cortisol and aldosterone production. In the mid-1990s, AIs with much greater specificity for the aromatase enzyme were developed, which produced no clinically relevant suppression of cortisol or aldosterone. These third-generation AIs include the steroidal drug exemestane, which binds irreversibly to the aromatase enzyme, and the nonsteroidal drugs letrozole and anastrozole, which form covalent, reversible bonds. Despite this slight difference in mechanism of action, both classes of drugs are very potent inhibitors of aromatase and have been shown to decrease estrogen levels to below the lower level of detection of most clinical assays [5 –8].

The third-generation AIs initially gained US Food and Drug Administration (FDA) approval for second-line treatment of metastatic, HR-positive breast cancer. Anastrozole, letrozole and exemestane were each shown to be equivalent or superior to megestrol acetate in women with metastatic breast cancer whose tumors had progressed on tamoxifen [9 –13]. Given their favorable side-effect profile, the drugs became widely used in the metastatic setting. Each of these drugs has also been compared with tamoxifen as a first-line therapy for advanced breast cancer [14 –18]. The AIs were found to have equivalent to slightly superior efficacy to tamoxifen and were granted FDA approval for use as first-line therapy of advanced HR-positive breast cancer.

Given the effectiveness of the AIs in metastatic disease, multiple adjuvant trials have been launched over the past decade. Five major trials have been reported to date, each involving several thousand patients (Table 1). The Anastrozole or Tamoxifen Alone or in Combination (ATAC) trial [19] and the Breast International cancer study Group's (BIG) 1–98 trial [20] have compared AIs with tamoxifen as initial hormonal therapy in the adjuvant setting, whereas the Intergroup Exemestane Study (IES) [21] and the Austrian Breast & Colorectal Cancer Study Group (ABCSG) Trial 8/German ARimidex NOlvadex (ARNO) 95 trial [22] have examined the impact of crossing women over to an AI after 2–3 years of tamoxifen. Finally, the MA-17 trial studied the use of an AI after 5 years of tamoxifen [23].

Table 1.

Large randomized trials of the aromatase inhibitors in the adjuvant setting.

Trial	Treatment strategy	Median follow-up	Aromatase inhibitor	Primary end point	Results	Ref.
ATAC	Initial hormonal therapy	68 months	Anastrozole	Disease-free survival*	HR of 0.83 (95% CI: 0.73–0.94) for the anastrozole arm	[19]
BIG 1–98	Initial hormonal therapy	25.8 months	Letrozole	Disease-free survival†	HR of 0.81 (95% CI: 0.70–0.93) for the letrozole arm	[20]
IES	Crossover from tamoxifen after 2–3 years	30.6 months	Exemestane	Disease-free survival*	HR of 0.68 (95% CI: 0.56–0.82) for the exemestane arm	[21]
ABCSG/ARNO	Crossover from tamoxifen after 2 years	36 months	Anastrozole	Event-free survival‡	HR of 0.60 (95% CI: 0.44–0.81) for the anastrozole arm	[22]
MA-17	Extended hormonal therapy after 5 years of tamoxifen	28 months	Letrozole	Disease-free survival‡	HR of 0.57 (95% CI: 0.43–0.75) for the letrozole arm	[23]

Locoregional or distant recurrence, contralateral breast cancer, or death

†

Locoregional or distant recurrence, any second breast or nonbreast malignancy, or death

‡

Locoregional or distant recurrence, or contralateral breast cancer.

ABCSG: Austrian Breast & Colorectal cancer Study Group; ARNO: ARimidex NOlvadex; ATAC: Anastrozole or Tamoxifen Alone or in Combination; BIG: Breast International Group; HR: Hazard ratio; IES: Intergroup Exemestane Study.

Initial hormonal therapy

The ATAC trial randomized 9366 postmenopausal women with invasive breast cancer to 5 years of adjuvant anastrozole, tamoxifen or a combination of the two [19]. Primary end points were DFS and tolerability. Baseline characteristics were well balanced across the three groups. The average age was 64 years, a third of the patients had positive lymph nodes and 64% had tumors smalled than 2 cm. Almost 84% of patients had ER-positive tumors, and another 8% had unknown receptor status. Only 8% of patients were known to be ER-negative, and these patients were equally distributed across the three arms. Prior treatments were also similar between the groups: 48% had undergone mastectomy, 62% had received radiation and 21% had been treated with chemotherapy.

An interim analysis was published after 33.3 months median follow-up. At that time, a total of 1079 events had occurred: 317 in the anastrozole arm, 379 in the tamoxifen arm and 383 in the combination arm. There was a statistically significant improvement in DFS in the patients treated with anastrozole compared with tamoxifen, with a hazard ratio (HR) of 0.83 (95% confidence interval [CI]: 0.71–0.96). There was no difference in DFS between the combination and tamoxifen arms. There was also a significant decrease in the incidence of contralateral breast cancers in the anastrozole group compared with the tamoxifen group (odds ratio [OR]: 0.42; 95% CI: 0.22–0.79). Survival analysis was not carried out.

An update was recently published with 68 months of median follow-up, at which time only 8% of patients were still receiving a study drug [24]. The updated efficacy analysis showed a continued benefit of anastrozole, with a significant advantage in terms of DFS (HR: 0.87; 95% CI: 0.78–0.097). The absolute difference in events between the anastrozole and tamoxifen arms in the subset of known hormone receptor-positive patients was 3.3% at 6 years. The improvement in DFS resulted from a reduction in the risk of distant recurrences, local–regional recurrence and contralateral cancers. At the time of this most recent update, no difference in OS was present.

The BIG 1–98 trial also compared treatment with an AI and tamoxifen as initial adjuvant therapy in postmenopausal women [20]. Patients were randomized to one of four arms: 5 years of letrozole, 5 years of tamoxifen, 2 years of tamoxifen followed by 3 years of letrozole or 2 years of tamoxifen followed by 3 years of letrozole. Although crossover data are not yet available, preliminary results from the core analysis, comparing tamoxifen with letrozole as initial therapy, were reported at the St Gallen (Switzerland) conference in January 2005. This analysis included data from all participants in the study, with events on crossover arms censored after 2 years. The core analysis included 8010 randomized patients and the median follow-up was 25.8 months. Patient characteristics were well balanced between groups: the median age was 61 years, 41% of patients were node-positive, 64% of tumors were smaller than 2 cm, 63% of patients were ER- and progesterone receptor (PR)-positive, with another 14% ER-positive and PR unknown. Prior treatments were also similar: 25% of patients had received chemotherapy and 50% of patients had been treated with lumpectomy and radiation.

The trial's primary end point was DFS, which included local recurrence, distant metastasis, contralateral breast primary tumors, second nonbreast malignancy and death without recurrence. At the time of the initial analysis, there were significantly fewer events in the letrozole arm compared with the tamoxifen arm (8.8 vs 10.7%; p = 0.003). Distant recurrence was significantly more common in the tamoxifen group (5.8 vs 4.4%; p = 0.006), but there was no difference in OS. Of note, there was a nonsignificant increase in nonbreast cancer-related deaths in the letrozole arm, with an excess of cardiac and cerebrovascular deaths in this group.

Sequential therapy

Given the differing mechanisms of action of the AIs and tamoxifen, several groups have examined the utility of a crossover approach, switching to an AI after some period of tamoxifen use. In the IES, 4742 postmenopausal patients who were free of disease after 2–3 years of tamoxifen were randomized to complete a 5-year course of tamoxifen or cross over to exemestane for the duration of the 5-year course [21]. Again, baseline characteristics were well balanced between the groups: the average age was 64 years, 51% of patients were node-negative, 81% were known to be ER-positive and approximately 16.5% in each group had unknown ER status. Prior treatments were also similar: 32% of patients had received chemotherapy and the median duration of prior tamoxifen therapy was 2.4 years.

The trial's primary end point was DFS. At the time of publication, 449 first events had been reported: 183 in the exemestane arm and 266 in the tamoxifen arm. The HR for an event in the exemestane group was 0.68 (95% CI: 0.56–0.82), which corresponded to a 4.7% difference in event rates between the two groups. The exemestane group also had a significantly lower risk of distant relapse (HR: 0.66; 95% CI: 0.52–0.83) and contralateral breast primary tumors, with 20 new primaries in patients treated with tamoxifen and nine in patients treated with exemestane (p = 0.04). There was no difference in OS reported, with 93 deaths in the exemestane arm and 106 in the tamoxifen arm.

A similar trial design was employed in the ABCSG Trial 8/German ARNO 95 trial [22]. In both studies, participants with hormone receptor-positive breast cancer who had completed 2 years of adjuvant tamoxifen were randomized to either 3 years of anastrozole or an additional 3 years of tamoxifen. Given the similarities in trial design, the two trials were combined for analysis. A total of 3224 patients were randomized in both studies: 2262 in the ABCSG and 962 in the ARNO trial. Patient characteristics were well balanced between the anastrozole and tamoxifen groups: 70% of patients had a tumor size of less than 2 cm, 74% were node-negative, 94% of tumors were grade I–II and 81% of tumors were both ER- and PR-positive. The trial's primary end point was event-free survival (EFS), defined as freedom from locoregional recurrence, distant metastasis or contralateral breast cancer. Secondary outcomes included distant DFS and tolerability.

At 28 months median follow-up, 177 events had occurred. Patients in the anastrozole arm were found to have a statistically better 3-year EFS than those in the tamoxifen arm (95.8 vs 92.7%; p = 0.0009). Rates of locoregional recurrence and new breast primaries were relatively similar in the two groups, but there was a significantly lower risk of distant relapse with anastrozole (HR: 0.61; 95% CI: 0.42–0.87). There was no significant difference in OS at the time of this initial analysis.

Finally, the Italian Tamoxifen Anastrozole (ITA) trial also utilized a crossover design, in which patients who remained disease free after 2–3 years of treatment with tamoxifen were randomized to crossover to anastrozole versus continuing tamoxifen to complete a 5-year course [25]. Again, baseline characteristics were relatively well balanced: the average age in both arms was 63 years, 52–55% of patients had been treated with mastectomy and 67% of patients had been treated with chemotherapy. A total of 14% of patients in the tamoxifen arm had missing or unknown ER status versus only 8% in the anastrozole arm, but this difference was not statistically significant. The trial's primary end point was DFS, defined as freedom from locoregional or distant recurrence.

A total of 448 patients were enrolled in the ITA trial, making this substantially smaller than other trials examining the use of AIs in the adjuvant setting. With 36 months of median follow-up, women in the anastrozole arm had a significantly lower risk of developing a breast cancer recurrence than those in the tamoxifen arm (HR: 0.35; 95% CI: 0.18–0.68). The 3-year difference in recurrence-free survival was 5.8%, but no difference in OS was reported.

Extended hormonal therapy

The MA-17 trial randomized 5187 early stage breast cancer patients who had completed approximately 5 years of adjuvant tamoxifen to 5 years of letrozole versus placebo [23]. All participants had discontinued tamoxifen 3 months or less prior to enrollment in the protocol. The two groups were well balanced in terms of baseline characteristics: the average age was 62 years, 46% of patients had positive lymph nodes and 98% of women were known to have hormone receptor-positive cancers. Prior treatment was also well balanced: 46% of patients had received chemotherapy and 50% had undergone mastectomy. The trial's primary end point was DFS, defined as the time from randomization to locoregional recurrence, distant recurrence or contralateral breast cancer. Secondary end points included OS, quality of life (QoL) and tolerability.

The trial was stopped at the time of the first interim analysis, with a median follow-up of 2.4 years. At that time, there were a total of 207 events. The letrozole arm demonstrated a significantly greater 4-year DFS, with 93% of patients free of disease versus 87% in the tamoxifen arm (p < 0.001). A similar degree of benefit was seen in node-positive and -negative patients. At the time of the initial report, 73 deaths had been reported and there was no significant difference between the letrozole and placebo arms. However, an updated subgroup analysis at 33 months median follow-up demonstrated a borderline significant (p = 0.04) survival advantage in lymph node-positive patients treated with letrozole compared with those treated with placebo, suggesting that prolonged hormonal therapy may improve survival, particularly in higher-risk patients [26].

A smaller trial examining prolonged hormonal therapy was presented by the ABCSG at the 2005 American Society of Clinical Oncology (ASCO) Annual Meeting [27]. The ABCSG Trial 6 was initially designed to evaluate the benefit of combining aminogultethimide and tamoxifen compared with tamoxifen alone as hormonal therapy for postmenopausal women with hormone receptor-positive breast cancer. The trial did not demonstrate any additional benefit from this combination approach. The investigators subsequently rerandomized 856 patients who had completed 5 years of hormonal therapy to 3 additional years of anastrozole versus no treatment. At 5 years median follow-up, there were 86 subsequent breast cancer events, which were defined as locoregional recurrences, distant metastases or contralateral breast cancers. The HR for a subsequent breast cancer event in the anastrozole arm was 0.64 (95% CI: 0.41–0.99) compared with placebo. There was no difference in OS.

Toxicity & quality of life

Each of the major adjuvant trials, as well as several smaller studies, has looked at the toxicity of the AIs. Four of these large trials compared the side effects of an AI with those of tamoxifen; the ATAC and BIG 1–98 trials compared the AIs with tamoxifen as initial hormonal therapy, while the IES and ARNO trial compared side effects of AIs and tamoxifen in women who had already completed 2–3 years of tamoxifen. Only the MA-17 trial compared the side effects of an AI with placebo, giving a better estimate of the toxicity of the drugs, although all patients in this study were pretreated with tamoxifen.

In general, all studies have demonstrated that the AIs are well tolerated drugs with low rates of discontinuation due to adverse events. In the MA-17 trial, in which letrozole was compared with placebo in women who had been treated with 5 years of tamoxifen, there was no statistically significant difference in discontinuation rates between the two arms, with 4.5% of women treated with letrozole discontinuing treatment versus 3.6% in the placebo arm (p = 0.11) [23]. In the ATAC trial, in which anastrozole was compared with tamoxifen, fewer women discontinued anastrozole than tamoxifen secondary to adverse events (11.1 vs 14.3%; p = 0.0002) [19].

Two of these large randomized trials included QoL substudies to determine the impact of prolonged AI therapy on overall QoL and menopausal symptoms. The ATAC trial examined QoL over the first 2 years of therapy in a subset of 1021 patients [28]. Patients completed the functional assessment of cancer therapy – breast (FACT–B) and an endocrine subscale at baseline and at 3, 6, 12, 18 and 24 months. The trial demonstrated that overall QoL was similar in the tamoxifen and anastrozole arms throughout the course of the study. In both arms, the overall QoL scores improved from baseline to 24 months, whereas endocrine symptoms worsened between baseline and 3 months, then stabilized for the remainder of the study. The study also demonstrated that women treated with anastrozole experienced more vaginal dryness, loss of libido and dyspareunia than women treated with tamoxifen. Prior studies have also demonstrated that women treated with tamoxifen have a worsening of sexual function compared with those treated with placebo. Further study of the incidence and magnitude of sexual side effects with the AIs is necessary.

The National Cancer Institute of Canada CTG MA-17 trial also conducted a QoL sub-study in 3582 women [29]. Participants completed the medical outcomes study 36 item short-form general health survey (SF36) as well as a menopause-specific QoL questionnaire at baseline, 6 months and then annually for 3 years. The study examined changes in overall QoL scores and found that there was no difference between the letrozole and placebo arms at any point. Patients in the letrozole arm had significantly more vasomotor and sexual side effects, but all other domains, including memory changes, weight gain and depression, were similar in the letrozole and placebo groups.

Side effects

The five major trials also collected detailed toxicity data and demonstrated that many side effects were similar in the AI- and tamoxifen-treated groups. Vasomotor symptoms were the most common side effect experienced by trial participants in every study. Although several individual studies suggested fewer hot flashes in one of the two treatment groups, there was no consistent difference in number or severity of hot flashes or night sweats across the studies. In general, 30–60% of patients experienced vasomotor symptoms. Similar incidences of fatigue (30%), mood swings/irritability (10%), sleep disturbance (20%) and weight gain (22%) were also observed in the AI and tamoxifen arms of the ATAC, IES and BIG 1–98 trials. Of note, similar incidence of many of these side effects was also observed in the placebo arm of the MA-17 trial.

Several studies have indicated that musculoskeletal complaints are more common in patients treated with AIs than those receiving tamoxifen. The ATAC study demonstrated a 35.6% incidence of joint pain in the anastrozole arm versus 29.4% in the tamoxifen arm (p < 0.0001). The IES demonstrated a significantly higher proportion of patients with arthralgias and myalgias in the exemestane versus the tamoxifen arm (5.4 vs 3.6%; p = 0.01), and preliminary results from the European Tamoxifen and Exemestane Adjuvant Multicenter (TEAM) trial [30], comparing 5 years of tamoxifen with exemestane, showed significantly more bone and muscle aches in patients treated with exemestane.

Bone effects

There has been much interest in determining the impact of long-term AI use on bone. Sex steroids are known to be important in maintaining bone integrity. Estrogen is believed to be essential for preventing bone resorption and androgens have been shown to enhance bone formation. Tamoxifen can decrease bone loss in postmenopausal women, especially in trabecular bone. AIs, on the other hand, cause bone loss in animal models [31,32] and increase markers of bone turnover in the urine of healthy female volunteers [33]. The adjuvant AI trials have studied the impact of AIs on bone using different approaches. The IES and MA-17 trial examined the incidence of new osteoporosis, defined as a T-score (number of standard deviations below peak bone mass) of less than −2.5. In the IES, more patients in the exemestane arm developed osteoporosis than in the tamoxifen arm (7.4 vs 5.7%; p = 0.05), although this difference was only of borderline significance [21]. In the MA-17 trial, more patients in the letrozole arm developed osteoporosis than with placebo (5.8 vs 4.5%; p = 0.07), but again, results did not reach statistical significance [23].

Several trials have evaluated the impact of the AIs on bone through the incidence of fractures. The ATAC, BIG 1–98 and ARNO/ASCSG trials all showed significantly higher fracture rates in the AI arms. The ATAC trial, with the longest median follow-up at 68 months, demonstrated an 11% incident rate of fractures in the anastrozole arm versus 7.7% in the tamoxifen arm (p < 0.0001) [24]. The other adjuvant AI trials all have substantially shorter follow-up than the ATAC trial, making it impossible to compare fracture rates across trials. However, each trial demonstrated more fractures in patients treated with AIs compared with those treated with tamoxifen. This difference was statistically significant in the BIG 1–98 and ARNO/ABCSG trials, with 4.1% of letrozole patients in BIG 1–98 and 2.4% of the anastrozole patients in the ARNO/ASCSG trials sustaining a fracture [20,22]. Fracture rates in the tamoxifen groups were 3.7 and 1.2%, respectively. The MA-17 trial and IES showed numerically more fractures in the AI arms, but this did not reach statistical significance, possibly suggesting that prior treatment with tamoxifen might help to protect against fracture [21,23].

Early animal data have suggested that exemestane may lead to less bone loss than anastrozole and letrozole. Exemestane is a steroidal inhibitor of the aromatase enzyme complex. One of its metabolic products, 17-hydroexemestane, is believed to have androgenic properties, which have been postulated to lead to an increase in new bone formation. Studies in ovariectomized rats have demonstrated that animals treated with exemestane had less bone loss than those treated with letrozole or anastrozole [34]. Studies in healthy volunteers have also demonstrated that both steroidal and nonsteroidal AIs increase markers of bone resorption in the urine, but only exemestane also leads to increases in markers of new bone formation [33]. Lonning and colleagues conducted a randomized study of bone effects in 128 women with low-risk, early stage breast cancer treated with 2 years of exemestane versus placebo [35]. Primary end points of the study included changes in bone density at the hip and spine, as well as markers of bone turnover in the urine. The 3-year follow-up of the cohort was reported at the ASCO conference in June, 2004 (LA, USA). The authors demonstrated that patients treated with exemestane lost an average of 2.17% bone density at the thoracic spine and 2.72% at the hip/year. Patients treated with placebo lost 1.84% at the thoracic spine and 1.48% at the hip/year (p = 0.02 between groups at the hip). Both groups showed a nonsignificant decrease in T-scores over the 3-year course of the study; however, the difference between groups was not statistically significant. The study also confirmed the finding that exemestane patients demonstrate an increase in both urinary markers of bone resorption and bone formation. The clinical relevance of these findings remains uncertain.

Gynecologic effects

Several studies have evaluated the impact of AI use on the endometrium. Owing to its mixed ER agonism and antagonism, tamoxifen has been shown to exert a two- to three-fold increase in the risk of endometrial cancer, as well as increasing the incidence of vaginal bleeding and discharge [36]. The AIs function by decreasing estrogen to very low levels, and therefore would not be expected to stimulate the endometrial lining. In the ATAC trial, significantly fewer endometrial cancers developed in the anastrozole compared with the tamoxifen arm (3 vs 13; p = 0.02). Numerically more endometrial cancers were observed in the tamoxifen arms of the IES and BIG 1–98 trial, but these differences were not statistically significant.

Several substudies have also examined secondary end points to help determine the impact of AIs on the endometrium. The ATAC trial and another small study comparing exemetane with tamoxifen in the adjuvant setting have each examined the impact of these agents on endometrial thickness [37,38]. Both demonstrated that tamoxifen caused significant thickening of the endometrial lining whereas the AIs did not. The IES examined changes in endometrial thickness in women who crossed over from tamoxifen to exemestane [39]. The study demonstrated that endometrial thickness decreased in patients who crossed over to exemestane. One final study demonstrated that women who developed benign pathology during tamoxifen treatment (e.g. endometrial polyps or hyperplasia) were less likely to require repeat hysteroscopy or endometrial biopsy if they crossed over to anastrozole rather than continuing with tamoxifen [40].

Vascular effects

In addition to an increased risk of endometrial cancer, tamoxifen use has also been limited by its thrombogenic potential. Tamoxifen has been shown to increase the risk of venous thromboembolism in several trials [2,36,41]. To date, the AIs have not been associated with a similar clotting risk in the metastatic setting [9,11,42]. In the adjuvant setting, the ATAC trial and IES have demonstrated a significantly higher rate of venous thromboembolism in tamoxifen-treated patients compared with those treated with an AI (2.1 vs 3.5% in ATAC and 1.3 vs 2.4% in IES) [19,21]. There is also somewhat inconsistent evidence that tamoxifen may increase the risk of cerebrovascular events (e.g. stroke and transient ischemic attack). The NSABP P-1 and B-24 trials have raised the possibility that strokes may be more common in tamoxifen users [36,41]. However, Geiger and colleagues performed a recent case–control study comparing 179 breast cancer patients who developed a stroke after diagnosis with 353 controls, matched for age and year of breast cancer diagnosis [43]. The study showed no association between tamoxifen use and stroke risk (OR: 1.0; 95% CI: 0.6–1.6). Given the small number of strokes observed in the adjuvant AI trials, it is very difficult to draw firm conclusions regarding whether or not the drugs increase the risk of stroke. The ATAC trial demonstrated a lower risk of embolic stroke in patients treated with anastrozole compared with those treated with tamoxifen, but a similar decrease in stroke risk for patients treated with AIs was not observed in the IES.

Some concern has been raised that the AIs may lead to higher rates of cardiovascular disease with long-term use, given the adverse effect that estrogen deprivation may have on lipid profiles. At this time, although several trials have shown numerically higher rates of cardiovascular disease in patients treated with AIs, no statistically significant differences have yet been detected. Several trials have demonstrated an adverse impact on lipid profiles in patients treated with an AI, however, and longer follow-up is necessary to determine the impact of long-term estrogen deprivation on the cardiovascular system.

Expert commentary & future perspective

Given the number of potential adjuvant hormonal therapy strategies for postmenopausal women with early stage breast cancer, the ASCO convened a technology panel to provide recommendations for hormonal therapy use. The panel has met several times since its initial inception in 2002, and its most recent recommendations were published in March 2005 [44]. At that time, the consensus opinion was that postmenopausal women without contraindications to AI therapy should receive one of these drugs at some time during the adjuvant period. However, the ‘best’ use of an AI remains unclear. It is not known at this time if women are best served by starting an AI as initial therapy or by taking tamoxifen for a number of years followed by an AI. Further data from the crossover arms of the BIG 1–98 trial may provide an answer to this question, but it will be several years before these data are available. In the interim, three groups have designed models to evaluate the relative benefits of different treatment strategies [45,46]. A Markov model, presented by Burstein and colleagues at the ASCO meeting in June 2005, suggests that a crossover from tamoxifen to an AI after 2–3 years may be the preferred strategy for the typical patient in order to minimize the chance of recurrence over a 10–15-year time span [45]. While such models can be helpful in analyzing complex data from a number of sources, they do not substitute for randomized clinical trials and are highly dependent on a range of assumptions.

In conclusion, there is substantial evidence that the AIs are an effective adjuvant therapy in postmenopausal women with hormone receptor-positive breast cancer. Several trials have demonstrated a significant, although small, advantage to using these medications as initial adjuvant therapy after breast cancer diagnosis in place of tamoxifen. Other studies have demonstrated superior outcomes in patients crossed over to an AI after 2–3 years of tamoxifen, compared with those who completed a 5-year course of tamoxifen. One final trial has shown that treatment with an AI after 5 years of tamoxifen therapy also decreases the risk of recurrence and new breast primaries. Studies have also demonstrated that the drugs are well tolerated and discontinuation rates are low. Although long-term use of AIs may lead to osteoporosis and fracture, the drugs do not appear to be associated with an increase in the risk of endometrial cancer or thromboembolism.

Studies are currently ongoing to determine the optimal treatment strategy for postmenopausal women with hormone receptor-positive breast cancer. Until these data are available, the differing side-effect profiles of tamoxifen and the AIs make it difficult to devise a ‘one size fits all’ hormonal therapy regimen. Furthermore, different tumor types may be more or less sensitive to different hormonal strategies, although it remains unclear how best to individualize the treatment to the tumor. As advocated by the ASCO technology panel, it is reasonable to treat the majority of postmenopausal women with an AI as part of their adjuvant hormonal therapy, but physicians will need to weigh the risks and benefits of the various treatment options and design a treatment plan for each individual patient.

Executive summary

Five major randomized trials have contributed to our understanding of the role of the aromatase inhibitors (AIs) in the adjuvant setting.

Two of these trials, the Anastrozole or Tamoxifen Alone or in Combination (ATAC) trial and the International Breast Cancer Study Group's Breast International Group (BIG) 1–98 trial compared an AI with tamoxifen as initial hormonal therapy in the adjuvant setting.

Three other trials have assessed crossover strategies: the Intergroup Exemestane Study (IES) and the Austrian Breast & Colorectal Cancer Study Group (ABCSG) Trial 8/German ARimidex NOlvadex (ARNO) 95 trial evaluated a crossover to an AI compared with continued tamoxifen therapy in women who had completed 2–3 years of tamoxifen.

The MA-17 trial examined the use of an AI compared with placebo after 5 years of tamoxifen.

The primary end point of these trials was disease-free or event-free survival, although the precise definition of this end point varied somewhat across trials. Regardless of the exact definition, each trial demonstrated a decrease in breast cancer events in women who had received an AI.

The five trials used the AIs at different times during the adjuvant period, raising questions about whether the lowest risk of recurrence occurs with an AI as initial hormonal therapy or following 2–5 years of tamoxifen.

The AIs are well-tolerated drugs with low rates of discontinuation due to adverse events.

Quality of life and vasomotor side effects are similar between tamoxifen and the AIs, while osteoporosis and fracture are more common with the AIs, and endometrial abnormalities and thromboembolism are more common with tamoxifen.

Future trials will help clarify whether initial therapy with an AI or sequential therapy with an AI before or after tamoxifen represents the optimal hormonal therapy for postmenopausal women with early stage breast cancer.

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Aromatase Inhibitors in the Adjuvant Treatment of Postmenopausal Women with Early Stage Breast Cancer

Abstract

Keywords

Initial hormonal therapy

Sequential therapy

Extended hormonal therapy

Toxicity & quality of life

Side effects

Bone effects

Gynecologic effects

Vascular effects

Expert commentary & future perspective

References