Annals of Oncology Advance Access originally published online on August 9, 2007
Annals of Oncology 2008 19(1):16-27; doi:10.1093/annonc/mdm282
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The breast cancer continuum in hormone-receptor–positive breast cancer in postmenopausal women: evolving management options focusing on aromatase inhibitors
1 University of California San Francisco, Comprehensive Cancer Center, San Francisco, USA
* Correspondence to: Dr H. S. Rugo, Clinical Professor of Medicine, Hematology & Oncology, Director, Breast Oncology Clinical Trials Program, UCSF Comprehensive Cancer Center, Carol Franc Buck Breast Care Center, 1600 Divisadero Street, 2nd floor, San Francisco, CA 94115-1710, USA; Tel: +1 415-353-7428; Fax: +1 415-353-9571; E-mail: hrugo{at}medicine.ucsf.edu
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Abstract |
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There are now a number of highly effective options for the treatment of hormone-receptor–positive breast cancer. Although tamoxifen was the standard hormonal treatment for many years, we now have another option for postmenopausal women: the third-generation aromatase inhibitors (AIs) anastrozole, exemestane and letrozole. A number of trials have investigated the use of third-generation AIs compared with tamoxifen throughout the continuum of treatment settings for postmenopausal women with breast cancer. In the neoadjuvant setting, letrozole, given for 4 months, resulted in better overall clinical response and breast-conserving surgery rates than tamoxifen. The Immediate Preoperative Anastrozole Tamoxifen or Combined with Tamoxifen trial gave anastrozole for 3 months with no difference in clinical response but significantly improved breast-conserving surgery rates. Compared with tamoxifen, anastrozole and letrozole significantly improved disease-free survival as early adjuvant treatment for hormone-receptor–positive disease. Switching to anastrozole or exemestane after 2 to 3 years of adjuvant tamoxifen for a total of 5 years of therapy was also more effective than continued tamoxifen. All three agents are approved in the early adjuvant or switching setting in the USA. Letrozole following 5 years of tamoxifen as extended adjuvant treatment improved disease-free survival and, in the node-positive subgroup, overall survival when compared with placebo. Anastrozole and letrozole are both approved for the first-line treatment of hormone-sensitive advanced breast cancer in postmenopausal women; letrozole showed an improved response rate compared with tamoxifen. Anastrozole, letrozole and exemestane are all indicated for the second-line treatment of advanced breast cancer. In summary, third-generation AIs have been shown to have superior efficacy over tamoxifen in the metastatic, neoadjuvant and adjuvant settings and to improve outcome as extended adjuvant therapy following 5 years of tamoxifen. Ongoing studies will further define the role of sequential adjuvant treatment. Appropriate duration of treatment is another important area of investigation. This review will cover hormonal therapy for postmenopausal women with breast cancer and will not address the treatment of premenopausal women.
Key words: anastrozole, aromatase inhibitors, breast cancer, exemestane, letrozole, tamoxifen
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TopAbstractintroductiontreatment of HR+ early-stage...treatment of HR+ advanced...cross-resistanceconclusionsAcknowledgementsReferences |
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Hormone-receptor (HR) status is an important factor used to determine the prognosis and treatment of breast cancer. HR-positive (HR+) breast cancer is defined as estrogen-receptor–positive (ER+), progesterone-receptor–positive (PgR+) or both. A patient with hormone-sensitive breast cancer has HR+ disease, which responds to treatments that specifically block or interfere with the function of estrogen or progesterone. The major source of estrogen in premenopausal women is the ovaries; in postmenopausal women, estrogen arises from the aromatization of peripheral androgens catalysed by the enzyme aromatase. The ovaries, adrenal gland and adipose tissue are the main sources of the peripheral androgens in postmenopausal women [1, 2].
Historically, the first evidence of effective hormonal therapy for breast cancer was the response of metastatic disease to ovarian suppression. Only about one-third of patients responded to this therapy, indicating that better identification of responsive cancers and more specific treatment was needed [3]. Sensitive tumors are now identified by testing for specific receptors. Hormone receptor testing is performed on either paraffin-embedded or frozen tumor tissue with immunohistochemical (IHC) staining [4, 5]. The degree of hormone positivity can be scored by a variety of methods; the best validated system is the Allred score. The Allred score combines a proportion score (PS) with an intensity score (IS) to arrive at a total score for receptor positivity (TS, range 0–8). The PS reflects the estimated proportion of positive tumor cells on the entire slide (range 0–5). The IS reflects the average staining intensity of positive tumor cells (range 0–3) [6]. However, due to ease of interpretation, the majority of laboratories report results as positive or negative, with a percentage of positive cells and the degree of intensity of staining. Central retesting has demonstrated that at least a modest percentage of results from IHC may be false negatives; negative testing that does not correlate with the biologic features of a tumor should be repeated [7, 8]. Studies to date have not determined a definitive connection between the relative degree of receptor positivity and response to hormone therapy, although clearly, minimally receptor-positive tumors have a lower chance of response [6]. Approximately 75% of breast cancers are ER+ and 55% are PgR+ [9, 10]. Endocrine therapy is indicated as part of adjuvant treatment for these tumors [11].
Treatment of established cancers depends on menopausal status. The estrogen pathway can be targeted through either receptor blockade, reduction of circulating estrogen levels in premenopausal women or suppression of estrogen synthesis in the tissues in postmenopausal women. Ovarian ablation alone or in combination with endocrine manipulation is an effective therapy for premenopausal women [12]. Although levels of circulating estradiol are about 10-fold lower in postmenopausal women than in premenopausal women, tissue estradiol levels are elevated due to conversion of weak androgens to estrogens via the aromatase enzyme [2], and are sufficient to support the growth of hormone-sensitive tumors. Targeting the estrogen pathway is a highly effective therapy for the most common type of breast cancer, and there are several agents now available (Table 1).
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Tamoxifen is a selective ER modulator (SERM) with both antagonistic and agonistic ER effects [13, 14]. At least part of the determination of effect is organ-based. In the breast, tamoxifen inhibits estrogen activity. However, tamoxifen has estrogen-like activity in the uterus and bone, resulting in endometrial hyperplasia and an increased risk of endometrial cancer, as well as preservation of bone mineral density in postmenopausal women [15, 16]. Despite the significant and durable efficacy of tamoxifen, it is this variability that also limits the benefits of tamoxifen as a treatment for breast cancer and contributes to its short-term side effects. Aromatase inhibitors (AIs), including anastrozole, letrozole and exemestane, selectively inhibit enzymatic aromatase activity in peripheral tissues responsible for estrogen synthesis in postmenopausal women. Anastrozole and letrozole are nonsteroidal inhibitors, and exemestane is a steroidal inhibitor with a different binding site on the aromatase enzyme. Fulvestrant, a pure ER antagonist without partial agonist activity, results in a significant reduction in cellular levels of the estrogen receptor [17].
Several different approaches comparing AIs with tamoxifen to treat early-stage breast cancer have been evaluated. Neoadjuvant therapy is given prior to surgery to reduce tumor load and improve the chances of breast-conserving surgery and the operability of larger tumors. In addition, treatment in the neoadjuvant setting allows assessment of clinical response, and it is possible to obtain serial tumor tissue to better understand determinants of response or resistance to specific therapies. Adjuvant AI therapy following primary surgery with or without chemotherapy has been tested in a number of ways: as initial therapy compared with tamoxifen for 5 years, as sequential therapy following 2–3 years of tamoxifen for a total of 5 years of hormone treatment, and following 5 years of tamoxifen as extended adjuvant therapy for 5 additional years. This review will examine the evolution of hormone therapy as treatment for postmenopausal women with early-stage breast cancer as part of the continuum of treatment for HR+ breast cancer.
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treatment of HR+ early-stage breast cancer |
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neoadjuvant therapy
In HR+ postmenopausal women, neoadjuvant endocrine therapy is an alternative for larger tumors when chemotherapy is not possible due to medical contraindications, or when surgery is delayed for a variety of reasons [18]. In addition, endocrine therapy may be preferred over chemotherapy for older women with tumors that are strongly HR+. The results of a comparison of neoadjuvant chemotherapy (four cycles of doxorubicin and paclitaxel) with neoadjuvant hormonal therapy (either anastrozole or exemestane for 3 months) in postmenopausal women with HR+ breast cancers showed similar clinical and pathologic complete response rates between the chemotherapy and hormonal therapy arms [19]. Significantly more patients were rendered eligible for breast-conserving therapy in the hormonal therapy arm (34%) compared with the chemotherapy arm (24%) [20]. Chemotherapy was associated with expected side effects such as grade III/IV alopecia, neutropenia, diarrhea and cardiotoxicity, while hormonal therapy was better tolerated, with the most common adverse events being hot flushes, vaginal discharge and musculoskeletal disorders [19]. Retrospective evaluation of patients in a variety of clinical trials have suggested that HR+ tumors may be less likely to respond to neoadjuvant chemotherapy [21], with very low rates of complete pathologic response. It is possible that neoadjuvant hormonal therapy offers an advantage over chemotherapy for hormone-sensitive tumors. At the present time, this should be considered as an important treatment option for older women with strongly HR+ tumors for whom neoadjuvant therapy is planned. In the future, genomic analysis should allow differentiation of hormone-sensitive tumors that do not require chemotherapy from those that should be treated with chemotherapy preferentially.
In two separate randomized clinical trials, 4 months or 3 months of neoadjuvant letrozole (PO24) or anastrozole (the Immediate Preoperative Anastrozole Tamoxifen or Combined with Tamoxifen [IMPACT] trial), respectively, improved the rate of patients receiving breast-conserving surgery compared with the same duration of therapy with tamoxifen. After 4 months of letrozole or tamoxifen, patients receiving letrozole had a significantly higher rate of breast-conserving surgery, 45% versus 35%, respectively (P = 0.022) [22]. Similar results were reported in the IMPACT trial in patients who were initially deemed ineligible for breast-conserving surgery. After 3 months of treatment, 46% of anastrozole patients became eligible for breast-conserving surgery, compared with 22.2% of patients receiving tamoxifen (P = 0.03) [23]. A recent report of a small (n = 151) randomized trial investigating exemestane in the neoadjuvant setting also found exemestane to be more effective than tamoxifen in terms of rate of clinical overall response (exemestane 76.3% vs tamoxifen 40%; P = 0.05) and breast-conserving surgery (exemestane 36.8% vs tamoxifen 20%; P = 0.05) [24].
Overall response (OR) is an important and clinically relevant end point in patients receiving neoadjuvant treatment due to the strong correlation of pathologic response and long-term outcome in chemotherapy trials [25]. In these neoadjuvant trials, clinical response was the primary end point. Pathologic response was not reported. Clinical OR did not differ significantly in patients receiving 3 months of anastrozole compared with tamoxifen in two neoadjuvant trials [23, 26]. In contrast, treatment with letrozole for 4 months resulted in significant superior OR compared with tamoxifen [22, 27].
Initial tumor size did not affect response rates; response was improved in both large and small tumors [22]. It may be that the duration of therapy influences the response to hormone therapy. Data from trials testing AIs as neoadjuvant therapy for breast cancer are summarized in Table 2.
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There is great interest in understanding the factors that may contribute to tamoxifen resistance or, more importantly, improved response to AIs. Two areas of interest are the relative intensity of ER and coexpression of other receptors that may lead to tamoxifen resistance. In an analysis of response rates based on degree of ER positivity using the Allred score, treatment with letrozole resulted in consistently higher response rates compared with tamoxifen in patients whose tumors had low ER scores [27]. In addition, a subset analysis demonstrated that letrozole was also significantly more effective than tamoxifen (OR 88% vs 21%; P = 0.0004) in ER+ patients whose tumors were found to have gene amplification for two factors linked to endocrine-therapy resistance, human epidermal growth factor receptor-2 (HER-2/neu [ErbB-2]) and human epidermal growth factor receptor-1 (HER-1, ErbB-1 or epidermal growth factor receptor) [28]. A similar subset analysis of patients enrolled in the IMPACT trial analysed response rates in tumors with HER-2/neu gene amplification and found that treatment with anastrozole resulted in higher response rates compared with tamoxifen in this high-risk population. Interestingly, subsequent studies have indicated that the presence of HER2/neu receptor overexpression is likely associated with relative resistance to at least most forms of hormone therapy, and that the growth stimulatory effects of the HER2 pathway overcome the effects of therapy directed to the ER. Further evaluation of the P024 neoadjuvant trial data indicated no real difference in suppression of proliferation as measured by Ki67 when comparing tamoxifen to letrozole in HER2 amplified tumors [29]. Data from the TransATAC group, described below, supports the overall worse outcome in this group of patients with early stage disease regardless of hormone therapy.
early (or initial) adjuvant therapy
The American Society of Clinical Oncology (ASCO) guidelines (Technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer) were updated based on the results of several large adjuvant trials, outlined in Table 3. These guidelines, published in early 2005, state that optimal adjuvant hormonal therapy for postmenopausal women with HR+ disease should include an AI either as initial therapy or following a course of tamoxifen [30]. The Arimidex, Tamoxifen Alone or in Combination (ATAC) trial was the first to show that the AI anastrozole was more effective than tamoxifen as initial adjuvant therapy for early-stage breast cancer [31–33]. This double-blind trial originally randomized 9366 postmenopausal women with ER/PgR+ or unknown receptor status breast cancer to 5 years of anastrozole, tamoxifen or a combination. The primary end point was disease-free survival (DFS), defined as the time to the earliest occurrence of local or distant recurrence, new primary breast cancer or death from any cause. Eighty-four percent of patients were HR+ and 8% were HR–, while in 8% of patients the receptor status was unknown. Sixty-five percent of patients had node-negative breast cancer and 22% received adjuvant chemotherapy [31]. At the first follow-up analysis with a median follow-up of 33 months, DFS in patients enrolled on the combination arm was found to be similar to that of tamoxifen alone, while treatment with anastrozole resulted in improved results. Subsequently, the combination arm of the ATAC trial was closed. The 6421 patients enrolled in the single-agent arms remained blinded and continued to be analysed for the primary and secondary end points. After a median follow-up of 68 months, anastrozole was associated with a 13% relative improvement in DFS over tamoxifen (P = 0.01) and a 21% relative risk reduction in time to recurrence (TTR) (P = 0.0005) [33]. This effect was greater in the HR+ subset, with a 17% improvement in DFS (P = 0.005) and a 26% risk reduction in TTR (P = 0.0002). A significant relative reduction in the risk of distant recurrence in the intent-to-treat (ITT) population (14%; P = 0.04) was observed, although the reduction in the HR+ population was not statistically significant (P = 0.06) [33]. Anastrozole reduced the incidence of new contralateral breast cancer in all patients (risk reduction 42%; P = 0.01) and in HR+ patients (risk reduction 53%; P = 0.001). In a subset analysis, anastrozole did not provide a significant advantage in terms of DFS for women with node-positive disease or for those treated with adjuvant chemotherapy.
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A more recent analysis investigating the use of different chemotherapeutic regimens used in the ATAC trial again showed no significant benefit for anastrozole over tamoxifen in these patients regardless of type of regimen [34]. At 68 months of median follow-up, there was no overall survival difference for either the ITT or HR+ populations (hazard ratio 0.93; P = 0.7) [33]. With respect to safety, patients taking anastrozole experienced an increased incidence of fractures, osteoporosis and musculoskeletal problems, while they experienced fewer gynecological problems and vascular events than those taking tamoxifen [33]. The incidence of hypercholesterolemia was higher in patients receiving anastrozole than in patients receiving tamoxifen (9% vs 3%; P <0.0001, respectively), and patients receiving anastrozole also had a slightly higher incidence of ischemic cardiovascular disease (4.1% vs 3.4%; P = 0.1) [33, 35].
A retrospective analysis of patients randomized on the ATAC trial initially suggested that a subset of patients may particularly benefit from the use of AIs as adjuvant therapy [36]; patients reported to have ER+/PgR– tumors experienced a statistically significantly improvement in DFS from treatment with anastrozole. However, the TransATAC group recently presented a central analysis of estrogen and progesterone receptors in a subset of patients enrolled in ATAC, and found no difference in the DFS benefit of anastrozole over tamoxifen based on PgR status (all patients hazard ratio [HR] 0.72, ER+/PgR+ HR 0.72, ER+/PgR– HR 0.66). In addition, HER-2/neu positivity was associated with a shorter time to relapse for both tamoxifen (P = 0.001) and anastrozole (P <0.0001) [37].
The Breast International Group (BIG) 1-98 trial [38] is the only study that is designed to compare initial adjuvant therapy with either an AI or tamoxifen with sequential use of both agents for a total duration of 5 years. This double-blind, randomized, Phase III study was initially started by Novartis in 1998 as a two-arm study called the Femara–Tamoxifen trial. The sequencing arms were then added when the International Breast Cancer Study Group (IBCSG, a subgroup of the BIG) took over the scientific integrity, operations and logistics of what then was renamed BIG 1-98. The primary end point, DFS, is defined as events occurring from the time of randomization to the time of either recurrence of the primary breast cancer at any local, regional or distant site, development of a new primary invasive breast cancer in the contralateral breast, development of any second primary cancer except basal or squamous cell carcinoma of the skin, or death from any cause. Unlike the ATAC study, the DFS end point in BIG 1-98 also includes secondary cancers. In this double-blind study, postmenopausal women with ER+ or PgR+ early-stage breast cancer were randomized to receive monotherapy with either letrozole or tamoxifen for 5 years or sequential administration of tamoxifen for 2 years followed by letrozole for 3 years, or letrozole for 2 years followed by tamoxifen for 3 years (Figure 1). The primary core analysis of 8010 patients included patients enrolled in all four arms of the trial, censoring patients in the sequential arms within 30 days of the 2-year switch, and was recently published [38]. Forty-one percent of patients had node-positive disease, and 25% received adjuvant chemotherapy. HR positivity was a requirement for study entry; 99.8% of patients had receptor-positive tumors.
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After a median follow-up of 25.8 months, with more than 1200 patients followed for at least 5 years, treatment with letrozole resulted in superior DFS than did treatment with tamoxifen, reducing the overall relative risk of recurrence by 19% (P = 0.003). Initial treatment with letrozole also significantly reduced the relative risk of distant metastases in HR+ tumors (27% reduction; P = 0.0012). Interestingly, prospectively planned subset analysis of the BIG 1-98 data revealed different information compared with ATAC. A significant improvement in DFS was observed in patients with node-positive disease as well as in patients who had received adjuvant chemotherapy. In addition, letrozole was superior to tamoxifen in all HR subsets, with an improvement in DFS in ER+/PgR+ and ER+/PgR– tumors. As was done in ATAC, HR status was determined locally, so the validity of both subset analyses has been questioned in terms of their value in establishing a population with relative hormone resistance based on receptor status. Central confirmation of receptor status was performed by the BIG and these data were recently presented [39], demonstrating benefit of letrozole over tamoxifen in the two HR+ subsets irrespective of PgR and HER-2 status. Patients with HER-2/neu–positive disease experienced a worse DFS than those with HER-2–negative tumors. At the current period of follow-up there was no significant difference in overall survival between the two groups (hazard ratio = 0.86; 95% confidence interval [CI] = 0.70–1.06; P = 0.16) [38].
Side effects in the BIG 1-98 trial were largely as expected and similar to those reported in the ATAC trial. Elevation of cholesterol was listed as an event in 43% of patients taking letrozole versus 19% of those taking tamoxifen. However, more than 80% of elevations were grade 1 or mild, and cholesterol levels remained relatively stable in patients taking letrozole, whereas treatment with tamoxifen resulted in a 12% overall reduction, suggesting that the observed difference between letrozole and tamoxifen in hypercholesterolemia in BIG 1-98 may be due to the lipid-lowering effects of tamoxifen. In comparison with tamoxifen, patients treated with letrozole had less vaginal bleeding and fewer thromboembolic complications. Conversely, letrozole increased the incidence of bone fractures and arthralgia compared with tamoxifen. Grade 3–5 cardiovascular events were reported in 3.7% versus 4.2% of the patients in the letrozole arm versus the tamoxifen arm, respectively, but grade 3–5 cardiac events were slightly but significantly more frequent in the letrozole arm (2.1% vs 1.1%, respectively; P = 0.0003) [38]. This degree of detail in grade of toxicity was not provided for either ATAC or the Intergroup Exemestane Study (IES).
switching adjuvant therapy
The development of resistance to tamoxifen, as well as its toxicity over time, limit its effectiveness and lead to preclinical data suggesting a possible benefit of switching from tamoxifen to an AI partway through tamoxifen therapy to decrease the risk of recurrence [40, 41]. Two of the AIs, exemestane and anastrozole, have been studied in this context; these data are summarized in Table 4 [42]. The IES [43, 44] compared switching to exemestane after 2 to 3 years of tamoxifen with tamoxifen alone, for a total of 5 years of endocrine treatment in 4742 women with early-stage breast cancer. The primary end point, DFS, was defined as the time from randomization to recurrence of breast cancer at any site, diagnosis of a second primary breast cancer or death from any cause. Eighty-five percent of women were ER+ and 12% had unknown ER status; patients were declared ineligible if their tumors were known to be ER– [43]. At a median follow-up of 56 months, the switch to exemestane significantly improved DFS compared with 5 years of tamoxifen alone (hazard ratio = 0.75; P = 0.0001), corresponding to an absolute benefit of 3.5% at 5 years in the ER+/unknown population [44]. In these patients, changing to exemestane significantly reduced the relative risk of contralateral breast cancer by 44% (hazard ratio = 0.56; P = 0.04) and improved breast cancer-free survival (hazard ratio = 0.75; P = 0.00005) as well as survival free of distant disease. At the most recent update of this trial, there was a borderline overall survival benefit in the hormone-receptor–positive or unknown group (hazard ratio = 0.83; P = 0.05) when compared with tamoxifen [44]. Subgroup analysis revealed a benefit from the switch in all subgroups, including in ER+/PgR+ vs ER+/PgR–, node-positive versus node-negative and patients receiving adjuvant chemotherapy.
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The overall side-effect profile following the switch was similar to that seen in ATAC and BIG 1-98; there was a higher rate of osteoporosis (9.2 vs 7.2%, P = 0.01) and fracture (7% vs 4.9%; P = 0.003) in patients on the exemestane arm. Although the initial report of these data suggested that pretreatment with tamoxifen could have a protective effect on bone, this effect was lost with further follow-up. Patients on the exemestane arm also had a slightly higher risk of myocardial infarction (1.3% vs 0.8%; P = 0.08) [44]. When patients actually on medication were analysed, the difference in the number of myocardial infarctions occurring in patients on exemestane compared to those on tamoxifen was insignificant (0.6% vs 0.2%; P = 0.06) [44]. The difference in cardiovascular events seen when all AIs are compared with tamoxifen may be due to a cardioprotective effect of tamoxifen and needs to be evaluated with longer follow-up.
In the Arimidex–Nolvadex (ARNO) 95 and the Austrian Breast Cancer Study Group (ABCSG) 8 studies [45], 3224 women receiving tamoxifen for 2 years (n = 3123) were randomized to continue with tamoxifen for a total of 5 years. Although originally not planned together, the studies were combined despite small differences in entry criteria. All patients in the trials were HR+, 27% were node-positive, and no patients in the study received prior chemotherapy. The primary end point was event-free survival (EFS). Switching to anastrozole resulted in significantly improved EFS compared with the tamoxifen group (hazard ratio = 0.60; P = 0.0009) and significantly better distant recurrence-free survival (hazard ratio = 0.61; P = 0.0067); the advantage of switching to anastrozole versus continuing with tamoxifen therapy was independent of nodal status [45]. There was no difference in overall survival at 28 months of follow-up, although there were a limited number of events for survival assessment (59 deaths on tamoxifen and 45 deaths on anastrozole). The incidence of prespecified adverse events was low, but there were significantly more fractures in the anastrozole group compared with the group continuing on tamoxifen (2% vs 1%). Interestingly, there were no differences in the incidence of gynecologic adverse events.
The Italian Tamoxifen Arimidex (ITA) trial [46] is a small, randomized, open-label study of ER+, lymph node-positive, postmenopausal women, of whom approximately 45% had prior adjuvant chemotherapy. In this study 448 women who had received tamoxifen for 2 or more years went on to receive continued tamoxifen or anastrozole for a total of 5 years of treatment. At a median follow-up of 36 months, patients receiving anastrozole had a significant improvement in DFS compared with those continuing on tamoxifen (hazard ratio = 0.35; P = 0.001) but experienced more adverse events (203 vs 150, respectively; P = 0.04). However, patients receiving tamoxifen had significantly more serious adverse events (33 of 150 events vs 28 of 203 events; P = 0.04). The trial was not able to look at other end points such as the risk of distant metastases and the variability of time on tamoxifen before the switch (median 28 months; range, 20–40 months), and the open-label design limits further analyses. Switching to anastrozole was associated with less gynecological toxicity and fewer venous disorders when compared with tamoxifen, but lipid metabolism disorders were more frequent with anastrozole [46]. Although this trial reported a benefit from switching to an AI after about 2.5 years of tamoxifen, the larger IES and ABCSG/ARNO 8 trials have significantly more robust data sets due to patient number as well as study design.
Two ongoing trials are expected to provide further clarification of optimal adjuvant hormonal regimens for postmenopausal women with early-stage breast cancer. The Tamoxifen–Exemestane Adjuvant Multicenter trial (TEAM), which began in 2001, is comparing 5 years of exemestane treatment with 5 years of tamoxifen treatment as adjuvant hormone therapy in early-stage disease. Results from the IES, which showed that switching from tamoxifen to exemestane after 2 to 3 years improves DFS over tamoxifen treatment alone, prompted an amendment to the TEAM trial design to include a similar switch (Figure 2) [47]. In addition, analysis of the sequential adjuvant arms of BIG 1-98, in which 2 years of letrozole treatment is followed by 3 years of tamoxifen treatment or vice versa (Figure 1) [37], will provide crucial comparative data on the benefit of sequencing letrozole and tamoxifen compared with front-line therapy and will also clarify optimal sequencing strategies. Results from the switching arms of BIG 1-98 trial are expected in 2008.
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Data from all of the switching trials have demonstrated increased benefit for patients with HR+ disease who switch to an AI after 2 to 3 years of adjuvant tamoxifen compared with those continuing on a total of 5 years of tamoxifen therapy [43–46]. Currently, the decision on whether to start with an AI or to start with tamoxifen and switch to an AI later on is a subject of great debate. The greatest risk of recurrence for HR+ breast cancer is in the first 2–3 years following surgery [48]. While this may reflect general hormone resistance, it has been suggested as a reason to start with an AI rather than with tamoxifen, especially in the patient population at increased risk for recurrence (e.g., patients with node-positive disease). However, it may be that sequencing tamoxifen and AIs retains the benefits of both classes of agents and optimizes outcome in disease that is hormone-sensitive. Future studies and ongoing analysis of patient tumor samples from the ATAC and BIG 1-98 trials will analyse specific phenotypes to better understand whether particular risk groups are best treated with one approach rather than another (e.g., treatment of HER-2/neu–positive, HR-positive disease with AIs rather than with tamoxifen in the adjuvant setting based on the data from the neoadjuvant studies described above) and may clarify differences between response based on PgR status, although this may require genomic analysis. Finally, data from the sequential arms of the BIG 1-98 trial will help determine the optimal time to introduce an AI. This trial is particularly important, as patients are randomized to either switching or receiving therapy from the start at diagnosis, rather than after 2–3 years of treatment with tamoxifen, which of course eliminates those who relapse early. The TEAM trial has more inherent variability due to differences in study design between the participating centers, but will also provide additional data on the switching approach compared to up-front therapy.
extended adjuvant therapy
HR+ early-stage breast cancer is a chronic disease, with half of the recurrences and over half of the deaths occurring after completion of 5 years of tamoxifen therapy [11]. This ongoing risk of recurrence varies by stage at diagnosis [49]. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial demonstrated that extending adjuvant tamoxifen to 10 years resulted in a worsening of DFS compared with 5 years of tamoxifen due to competing morbidities and the probable development of resistance to tamoxifen over time [40]. MA.17 was the first study to demonstrate the benefit of an AI (letrozole) as extended adjuvant hormone treatment after 5 years of tamoxifen [50, 51]. In this trial, postmenopausal women (n = 5187) with HR+ early-stage breast cancer who were disease-free following 4–6 years of adjuvant tamoxifen were randomized to receive letrozole or placebo for 5 additional years as extended adjuvant therapy. Unlike the trials outlined above, women did not have to be postmenopausal at diagnosis; those who became amenorrheic during chemotherapy or tamoxifen treatment were allowed into the study. Almost one-half of patients enrolled in the trial had node-positive disease (45.3% of letrozole patients and 46% of placebo patients), and about half of the patients received adjuvant chemotherapy (45.6% of letrozole patients and 45.1% of placebo patients). The primary end point was DFS, defined as the time from randomization to the recurrence of the primary disease or the development of a new primary breast cancer in the contralateral breast. This trial was unblinded early in October 2003, following the prospectively planned first interim analysis at a median follow-up of 2.4 years, due to highly significant differences in outcomes between the letrozole and placebo groups [50]. In the final analysis, at 2.5 years median follow-up, letrozole was associated with significantly improved DFS, defined as recurrence or a contralateral breast cancer (hazard ratio = 0.58; 95% CI = 0.45–0.75; P < 0.001) [51]. Letrozole also significantly reduced the risk of distant metastases (hazard ratio = 0.60; 95% CI = 0.43–0.84; P = 0.002). There was no difference in overall survival between groups (hazard ratio = 0.82; 95% CI = 0.57–1.19), but a survival advantage was observed in the node-positive subgroup (hazard ratio = 0.61; 95% CI 0.38–0.98; P = 0.04), making letrozole the first AI to demonstrate a significant improvement in survival in early breast cancer. The occurrence of hypercholesterolemia (16% vs 16%; P = 0.79) and cardiovascular events (5.8% letrozole vs 5.6% placebo; P = 0.76) was similar between letrozole and placebo groups [51]. An increased incidence of new osteoporosis was observed with patients receiving letrozole (P = 0.003); however, the rate of clinical bone fractures was not statistically significant between the two treatment arms [51]. Statistically more patients receiving letrozole had hot flashes, anorexia, arthralgia and alopecia, while more placebo patients reported vaginal bleeding [51].
At the time of the unblinding in October of 2003, patients originally randomized to placebo were offered letrozole free of charge. A total of 1655 women chose letrozole, and 613 women chose no additional therapy [52]. Interestingly, patients choosing letrozole were younger, had a lower performance status and were more likely to have node-positive disease and have had treatment with adjuvant chemotherapy—an overall worse prognosis group. However, in this nonrandomized comparison, women who chose letrozole following a median of 2.5 years of placebo had statistically improved DFS, distant DFS and overall survival as well as less new contralateral breast cancer compared with those who chose no additional therapy. Treatment appeared safe, with an increase in new osteoporosis but no difference in bone fractures or cardiovascular disease. These very interesting data suggest that therapy with an AI, even at a median of 7.5 years following diagnosis, can significantly affect breast cancer outcome and is affecting late recurrences seen in HR+ breast cancer.
MA.17R is an ongoing study designed to evaluate continued therapy with letrozole for up to 15 years. Patients who are disease-free after completing 5 years of extended adjuvant letrozole (either in the MA.17 trial or routine clinical practice) and women completing 5 years of any adjuvant AI (as initial treatment or after any prior length of time on tamoxifen) will be offered re-randomization at year 10 to continue either letrozole or placebo for an additional 5 years [53].
Extended adjuvant letrozole therapy offers all women, even those at minimal risk, an opportunity to further reduce their ongoing risk of breast cancer recurrence following adjuvant tamoxifen treatment. Given the evolving data utilizing AIs in the adjuvant setting, this is particularly important for women who are premenopausal at diagnosis but become postmenopausal during tamoxifen treatment.
Results from the ABCSG 6a trial investigating extended adjuvant therapy with anastrozole were recently reported [54]. In this open-label study, postmenopausal women with node-positive disease who had received tamoxifen in combination with aminoglutethimide (n = 406) or tamoxifen alone (n = 450) were re-randomized to switch to anastrozole (1 mg/day) or no treatment for an additional 3 years. At 5-year follow-up, significantly fewer patients in the anastrozole group experienced disease recurrence compared with the placebo group (30 vs 56 patients; hazard ratio = 0.64; P = 0.047), but there was no statistically significant difference in survival between the two groups. These are the first data showing efficacy of anastrozole as an extended adjuvant therapy, but conclusions must be drawn carefully, because this was a small, open-label trial with unbalanced arms, and no safety results are presently reported.
The other large extended therapy trial, NSABP B-33, which compared exemestane with placebo for an additional 5 years of treatment following 5 years of treatment with tamoxifen, was closed early when the results of MA.17 were reported in 2003 [55]. At the time of study unblinding, 1598 patients out of the planned 3000 had been enrolled; 72% continued exemestane, and 44% of patients taking placebo changed to exemestane. With a median follow-up of only 30 months, and despite the crossover, extended adjuvant therapy with exemestane in B-33 resulted in a borderline improvement in DFS (relative risk = 0.68; P = 0.07) and a significant improvement in relapse-free survival (relative risk = 0.44; P = 0.004) [54]. Data from these three trials are summarized in Table 5.
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The 2006 Breast Cancer Guidelines of the National Comprehensive Cancer Network (NCCN) suggest that adjuvant hormonal therapy for HR+ postmenopausal women with tamoxifen alone should be limited to women in whom AIs are contraindicated or to those who decline treatment with AIs. Otherwise, the use of AIs is recommended in the early adjuvant (anastrozole or letrozole), sequential adjuvant (anastrozole or exemestane) and extended adjuvant settings (letrozole) where specific AIs have proven superior to tamoxifen [56]. The 2005 ASCO guidelines support the use of an AI in HR+ postmenopausal women with early breast cancer as a component of adjuvant therapy, although the optimal sequence and duration of therapy are as yet unknown [30]. As AIs become the standard of care for postmenopausal women with HR+ early-stage breast cancer, it will become critical to understand the long-term side effects and risks and to incorporate regular screening tests as well as appropriate preventive strategies. At the present time, bone mineral density and cholesterol should be monitored, and treatment provided as indicated by current guidelines [29, 56, 57].
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first-line therapy
Two identical, double-blind, randomized, multicenter trials were conducted in North America and in Europe, comparing first-line anastrozole with tamoxifen in 1021 postmenopausal women with locally advanced or metastatic breast cancer [58, 59]. Patients with known ER– tumors were excluded from both trials. There was a substantial difference in the percentage of confirmed HR+ patients between the two studies, with 89% in the North American study and 45% in the other. The primary end point was time to progression (TTP) [58]. Analysed together, the trials demonstrated that tamoxifen and anastrozole had similar efficacy with respect to TTP (hazard ratio = 1.13) [58]. However, women with known HR+ disease receiving anastrozole in the combined analysis fared better, with a median TTP of 10.7 months versus 6.4 months for the tamoxifen group (P = 0.022) [58]. Response rates were similar in both studies between the two arms, but in the North American trial, progression-free survival was longer in patients treated with anastrozole (11.1 months vs 5.6 months; P = 0.005 [59]. These differences can probably be attributed to the imbalance in HR+ subjects between the two studies. There was no difference in overall survival between the two arms of either study.
The European Organisation for Research and Treatment of Cancer (EORTC) evaluated exemestane or tamoxifen as first-line hormonal therapy in 382 patients with HR+ metastatic breast cancer in a randomized, open-label Phase III trial. Progression-free survival was the primary end point. In this trial 84%–88% of women had known HR+ disease. Exemestane significantly reduced the risk of progression relative to tamoxifen (hazard ratio = 0.84; P = 0.028, 9.9 vs 5.8 months) [60]. Objective response was higher in patients treated with exemestane than in patients treated with tamoxifen (46% vs 31%, respectively; odds ratio = 1.85; P = 0.005). Overall survival was similar between the two arms of the trial.
A Phase III, multinational, randomized, double-blind study evaluated letrozole or tamoxifen in 907 postmenopausal women with locally advanced or metastatic breast cancer. The primary end point was TTP, defined as the interval between the date of randomization and the earliest date of disease progression [61]. Compared with tamoxifen, letrozole significantly improved TTP (median, 9.4 vs 6.0 months; P < 0.0001), time to treatment failure (median, 9.0 vs 5.7 months; P < 0.0001) and OR (32% vs 21%; P = 0.0002). Similar to the two trials outlined above, there was no significant difference between the two arms in terms of overall survival [62]. However, significantly more patients on first-line letrozole therapy than on first-line tamoxifen therapy were alive at each 6-month interval during the first 2 years of treatment (all comparisons P < 0.025) [62]. A crossover trial was built into this study with prospectively planned survival analyses at 6-month intervals, which allowed patients to switch to the alternate hormone therapy after progression; 51% of letrozole patients and 49% of tamoxifen patients crossed over at a median of 32 months. The large number of patients crossing over potentially impaired the chance of seeing an overall survival advantage.
The survival results from this trial with the crossover design and the results of the trials outlined above indicate that hormone therapies should be offered in sequence for women with hormone-responsive advanced breast cancer, as there appears to be at least some degree of non–cross-resistance.
Fulvestrant is a pure ER antagonist or down-regulator without agonist properties that is approved as second-line therapy following tamoxifen in postmenopausal women with advanced breast cancer. In a randomized, double-blind, double-dummy, parallel-group, multinational study comparing 250 mg fulvestrant given as an intramuscular injection once a month with tamoxifen once daily (n = 587) as first-line therapy for advanced breast cancer in postmenopausal women, no significant difference was seen between groups for TTP or OR at a median follow-up of 14.5 months [63]. Treatment with fulvestrant in patients whose disease progressed after treatment with tamoxifen resulted in similar TTP and response rates compared with anastrozole [64], providing another treatment option for postmenopausal women with HR+ advanced breast cancer. Pharmacokinetic studies demonstrate that it takes approximately 3 months to achieve steady state levels in the serum of patients receiving monthly injections of fulvestrant [65], leading to a number of ongoing trials evaluating a loading dose of fulvestrant every 2 weeks for three doses, followed by monthly injections, as well as an evaluation of initial dosing at 500 mg. One recent study evaluated a loading dose of 500 mg of fulvestrant, following by 250 mg day 14 and day 28, followed by standard monthly dosing [66]. PK data demonstrated that steady state levels were achieved at one month, suggesting that this is a more appropriate and potentially effective method of administration. An ongoing cooperative group trial is comparing first-line fulvestrant to anastrozole utilizing the loading dose approach.
second-line therapy
The NCCN guidelines recommend the use of an AI in postmenopausal women with recurrent breast cancer who have received antiestrogen treatment within the past 12 months [56]. Another option for second-line endocrine treatment is fulvestrant, which has been shown to be as effective as anastrozole in patients whose disease progressed during tamoxifen treatment [67] (see above). Several studies have evaluated sequential hormone therapy and found small but consistent response regardless of the order in which therapy was administered [68–70]. The recently presented phase III EFECT trial evaluated sequential therapy with an AI compared to fulvestrant [66]. Six hundred and ninety three postmenopausal women with advanced HR+ breast cancer who had recurrent or progressive disease following treatment with a nonsteroidal AI were randomized to receive either exemestane or a modified loading dose of fulvestrant. Median TTP was 3.7 months in both groups; ORR and rate of CB were also identical. The median duration of response was quite long, ranging from 9.8 to 13.5 months and CB was seen in up to 29% of patients with visceral dominant disease, regardless of prior response to nonsteroidal AI. Again, this indicates that patients with hormone-sensitive breast cancer benefit from sequential administration of available hormone agents.
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Evidence of resistance to antiestrogens and AIs is evident from incomplete responses and recurrent or relapsing disease [71]. Maintaining options for further endocrine therapy is clinically important because of the sequencing regimens under study. Endocrine therapies are also generally better tolerated than chemotherapy, so the availability of endocrine treatment for relapsed/recurrent disease is an important area of study. Patterns of endocrine therapy resistance have been described [72]; understanding these patterns is important in order to assess responses to and potential benefits of endocrine therapies. Interestingly, patients will respond to further endocrine therapy even after their disease has progressed while on tamoxifen [73]. Little cross-resistance has been reported either between the antiestrogens and the AIs or within the group of AIs [68, 70, 74, 75]. Use of drugs such as fulvestrant with a novel mechanism of action may also help to reduce the development of cross-resistance [76]. Further study should provide information about the effect, if any, of cross-resistance between hormonal therapies and the potential impact of sequencing drugs used as hormonal therapy. Correlation of gene arrays to response and resistance to hormone therapy in patients with HR+ breast cancer will help to triage patients to appropriate therapies in the future. HER-2/neu overexpression has correlated with poorer overall outcome on hormonal therapy. The TrAstuzumab in Dual HER2 positive ER positive Metastatic breast cancer TAnDEM trial randomized women with HER-2/neu and ER+ untreated metastatic breast cancer to anastrozole with or without trastuzumab [77]. Although this study demonstrated a significant advantage for both response rate (6.8 vs 20.3%; P = 0.018) and progression-free survival (2.4 vs 4.8 months; P = 0.0016) with the addition of trastuzumab, the duration of response was still disappointingly short, and there was no difference in overall survival. These data suggest that hormonal therapy is perhaps best used following chemotherapy but with continued trastuzumab to maintain remission. Ongoing and planned clinical trials are evaluating the role of targeted therapies, including agents that target the HER-2/neu and epidermal growth factor receptors, angiogenesis and down-stream signaling in combination with AIs and fulvestrant to overcome resistance to therapy targeting the estrogen receptor.
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These data support the use of the third-generation AIs in place of or in sequence with tamoxifen as the new standard of treatment in women with early or advanced hormone-sensitive breast cancer. When used as adjuvant treatment in early breast cancer, AIs have improved DFS in several settings. The ATAC trial of anastrozole and the BIG 1-98 study of letrozole each demonstrated significantly prolonged DFS in the AI group compared with the tamoxifen group, but only letrozole showed significant DFS improvement for patients at increased risk of early recurrence (i.e., node-positive disease or chemotherapy-treated patients). Central analysis of primary tumor samples from patients enrolled in both the BIG 1-98 and ATAC trials showed a benefit for the AI in all patients with ER+ tumors irrespective of PgR status, indicating that treatment decisions for the use of AIs should not be made based on PgR status or on retrospective analysis of local tissue staining. Studies employing a switch to anastrozole or exemestane after 2 to 3 years of tamoxifen resulted in significantly less recurrence in patients who switched to the AI compared with those who remained on tamoxifen, with a borderline benefit for overall survival. Pending data from BIG 1-98 will compare a switch to letrozole at 2 years with upfront letrozole, as well as the reverse switch with tamoxifen. MA.17 is a landmark trial clearly showing that letrozole as extended adjuvant therapy provided continued protection from recurrence in patients who had already completed 5 years of tamoxifen, and it is the only AI to date showing improvement in survival in the node-positive subgroup. The Femara versus Anastrozole Clinical Evaluation trial is now under way to determine which nonsteroidal AI is superior in the adjuvant treatment of patients with node-positive tumors. In hormone-sensitive advanced or metastatic breast cancer, treatment with AIs in general resulted in improved TTP and improved response for letrozole and exemestane. Currently, anastrozole and letrozole are indicated for first- and second-line treatment of patients with HR+ or HR–/status unknown advanced/metastatic breast cancer, while exemestane is approved for second-line treatment.
Published guidelines now include the use of the third-generation AIs as adjuvant treatment alone or following a course of tamoxifen for postmenopausal women with HR+ disease [29, 56]. There are highly effective new options for the treatment of early- and late-stage HR+ breast cancer that have improved treatment options, DFS and TTP and have already been shown to improve survival in the extended therapy setting. It is important for oncologists and primary care physicians to understand the potential short- and long-term risks of these agents when used in the early-stage setting, so that appropriate testing and preventive treatment can be offered. Additional studies are evaluating the efficacy of the combination of ovarian suppression and AIs in premenopausal women.
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The author would like to thank Ms Sharon Thomas for her invaluable help in preparing this manuscript.
Received for publication July 27, 2006. Revision received May 12, 2007. Accepted for publication May 14, 2007.
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