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Breast Cancer |
Massachusetts General Hospital, Boston, Massachusetts, USA
Key Words. Breast cancer • Aromatase inhibitors • Adjuvant • Hormonal • Postmenopause • Perimenopause • Review
Correspondence: Paula D. Ryan, M.D., Ph.D., Massachusetts General Hospital,Cox 640, 100 Blossom Street, Boston, Massachusetts 02114, USA. Telephone: 617-726-5046; Fax: 617-724-3166; e-mail: pdryan{at}partners.org
Received January 19, 2006; accepted for publication June 2, 2006.
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LEARNING OBJECTIVES
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Learning Objectives
Abstract
Introduction
Tamoxifen as Adjuvant Therapy...
AIs as Adjuvant Therapy...
Tolerability Results
Skeletal Effects
Clinical Use of AIs...
Resistance to AIs in...
Conclusion
Disclosure of Potential...
References
After completing this course, the reader will be able to:
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ABSTRACT |
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TopLearning ObjectivesAbstractIntroductionTamoxifen as Adjuvant Therapy...AIs as Adjuvant Therapy...Tolerability ResultsSkeletal EffectsClinical Use of AIs...Resistance to AIs in...ConclusionDisclosure of Potential...References |
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INTRODUCTION |
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TopLearning ObjectivesAbstractIntroductionTamoxifen as Adjuvant Therapy...AIs as Adjuvant Therapy...Tolerability ResultsSkeletal EffectsClinical Use of AIs...Resistance to AIs in...ConclusionDisclosure of Potential...References |
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TAMOXIFEN AS ADJUVANT THERAPY OF POSTMENOPAUSAL BREAST CANCER |
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TopLearning ObjectivesAbstractIntroductionTamoxifen as Adjuvant Therapy...AIs as Adjuvant Therapy...Tolerability ResultsSkeletal EffectsClinical Use of AIs...Resistance to AIs in...ConclusionDisclosure of Potential...References |
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However, despite the improvement in survival observed with tamoxifen, at least two thirds of eligible women with hormone receptor-positive breast cancer do not appear to benefit from tamoxifen. More than 50% of breast cancer relapses and more than two thirds of deaths occur after the initial 5 years after surgery [1, 2]. Patients treated with 5 years of tamoxifen subsequently experience substantial rates of both new primary tumors and relapses at all sites, and these events are associated with ongoing mortality [3].
Substantial progress has been made in recent years in elucidating a molecular mechanism that may impart either primary or adaptive/acquired resistance to tamoxifen. Interactions between the classic estrogen-ER pathway and other nongenomic growth-promoting pathways (termed crosstalk) have been implicated as a general mechanism by which tumor cells may circumvent the primary receptor-blocking mechanism of tamoxifen. For example, tumors expressing high levels of human epidermal growth factor receptor (HER)-2 may be resistant to tamoxifen in preclinical models [4], presumed to be a result of enhanced crosstalk between the ER and HER-2 pathways [5]. In MCF-7 cells (a human breast cancer cell line studied extensively as a model for breast cancer growth) expressing high levels of ER and HER-2, both estrogen and tamoxifen induce activation of the ER, the epidermal growth factor receptor (EGFR)/HER-2, and growth-promoting signaling molecules [5] (Fig. 1
).
Adaptive resistance may, in part, be explained by the fact that tamoxifen has partial agonist effects on the ER but may also be a result of chronic estrogen deprivation. It has been shown that tamoxifen resistance is acquired if MCF-7 cells are cultured with tamoxifen for a prolonged period [6, 7]. In vitro and xenograft in vivo models in mice have shown that long-term exposure to tamoxifen causes MCF-7 cell-derived tumors to grow in response to either tamoxifen or very low doses of estrogen [8–10].
These resistance mechanisms may help explain some clinical observations that no additional efficacy has been demonstrated with >5 years of tamoxifen use, and the current clinical recommendation is for 5 years of tamoxifen therapy [11]. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial randomized 1,172 women who had completed 5 years of tamoxifen therapy to either a further 5 years of tamoxifen or placebo [12, 13]. Seven years beyond rerandomization, there was no additional benefit from prolonged tamoxifen; in fact, prolonged tamoxifen conferred a worse prognosis than discontinuing therapy at 5 years. One trial confirmed this finding and another did not [14, 15]. This, together with the laboratory observations, has led to the speculation that tamoxifen’s agonist action at the ER may lead to tumor growth stimulation over time. Two trials, the Adjuvant Tamoxifen Longer Against Shorter (ATLAS) and Adjuvant Tamoxifen Treatment Offer More? (ATTOM) trials, randomized patients to either 5 years of tamoxifen or longer, and the results of these trials will help answer this very important question of duration of tamoxifen therapy.
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AIS AS ADJUVANT THERAPY OF POSTMENOPAUSAL BREAST CANCER: EFFICACY RESULTS |
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TopLearning ObjectivesAbstractIntroductionTamoxifen as Adjuvant Therapy...AIs as Adjuvant Therapy...Tolerability ResultsSkeletal EffectsClinical Use of AIs...Resistance to AIs in...ConclusionDisclosure of Potential...References |
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). Updated efficacy followed by toxicity data are discussed in the following sections (Table 1, 2).
Upfront Therapy
Two large randomized trials have compared tamoxifen with AIs as initial adjuvant therapy. The Anastrozole or Tamoxifen Alone or in Combination (ATAC) trial randomized 9,366 postmenopausal women with ER+ or unknown invasive breast cancer to 5 years of adjuvant tamoxifen, anastrozole, or the combination of the two [21, 22]. There was no difference in disease-free survival (DFS) between the combination arm and the tamoxifen arm, and anastrozole was superior to both. With the most recent analysis at a median follow-up of 68 months, that study demonstrated a significantly lower risk for recurrence (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.78–0.97; p = .01) and longer time to recurrence (HR, 0.79; 95% CI, 0.70–0.90; p = .005) for anastrozole versus tamoxifen given for 5 years [23]. Anastrozole also resulted in significantly less distant metastasis (HR, 0.86; 95% CI, 0.74–0.99; p = .04) and significantly fewer contralateral breast cancers (42% less; 95% CI, 12%–62%; p = .01). Thus far, there have been no differences in the rates of death from any cause (HR, 0.97; 95% CI, 0.85–1.12; p = .7), and few breast cancer–related deaths have occurred. Based on the results of the ATAC trial, anastrozole is now approved by the U.S. Food and Drug Administration (FDA) as upfront adjuvant therapy.
The second large, upfront AI trial, the Breast International Group (BIG) 1–98 (n = 8010) study, compared letrozole with tamoxifen for 5 years, and results were published in December 2005 [24]. That study has four treatment arms: letrozole for 5 years, tamoxifen for 5 years, tamoxifen for 2 years then letrozole for 3 years, and letrozole for 2 years then tamoxifen for 3 years. The published analysis compares the two groups assigned to receive letrozole initially with the two groups assigned to receive tamoxifen initially. Events and follow-up in the sequential-treatment groups were included up to the time that treatments were switched. The results of the primary core analysis, with a median follow-up of 25.8 months, revealed that letrozole resulted in a significantly lower risk for recurrence (HR, 0.81; 95% CI, 0.70–0.93; p = .003), with 5-year DFS rate estimates of 84.0% for the letrozole group and 81.4% for the tamoxifen group. Letrozole resulted in significantly fewer recurrences at distant sites (HR, 0.73; 95% CI, 0.60–0.88; p = .001). Overall survival (OS) did not differ significantly between the two groups (HR, 0.86; 95% CI, 0.70–1.06; p = .16). Based on the results of that study, letrozole is now approved by the U.S. FDA for the adjuvant treatment of postmenopausal women with early breast cancer.
The Tamoxifen and Exemestane Adjuvant Multicenter (TEAM) trial has completed recruitment of approximately 4,400 postmenopausal patients with early-stage breast cancer, randomizing patients to exemestane or tamoxifen as adjuvant therapy for 5 years. Based on the results of the Intergroup Exemestane Study (IES) (see section below) showing that the sequence of exemestane after 2–3 years of tamoxifen produces superior DFS over that seen with tamoxifen alone, the TEAM trial has been amended to affect this sequencing.
AIs Used in Sequence
The National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) MA.17 trial was designed to determine whether extended adjuvant therapy with letrozole, beyond 5 years of tamoxifen, could further reduce the risk for late relapse and survival [25]. A total of 5,187 women was randomly assigned to letrozole or placebo. The study was stopped by the independent data safety monitoring committee after the first protocol-prespecified interim efficacy analysis with a median follow-up of 2.4 years. The interim analysis revealed that, after 207 events had occurred, there was a 4-year DFS rate of 93% for letrozole-treated patients versus an 87% DFS rate for the placebo arm (p < .001). Recently, an updated analysis of the MA.17 trial, at a median follow-up of 30 months, revealed the HR for recurrence or contralateral breast cancer in those patients receiving letrozole relative to those receiving placebo to be 0.58 (95% CI, 0.45–0.76; p = .001) [26]. Letrozole also led to significantly better distant DFS, represented by a 40% lower risk for distant recurrence in the letrozole group as compared with the placebo group (HR, 0.60; 95% CI, 0.43–0.84; p = .002). OS was the same for all patients in each arm (HR for death from any cause, 0.82; 95% CI, 0.57–1.19; p = .3). However, in a prespecified subset analysis, a statistically significant greater OS in lymph node-positive patients with letrozole therapy (HR, 0.61; 95% CI, 0.38–0.98; p = .04) was demonstrated. The annual incidence of contralateral breast cancer was substantially lower numerically: 4.8 per 1,000 patients for those receiving placebo and 3.0 per 1,000 for those receiving letrozole, but the difference was not statistically significant (difference of 1.8 per 1,000; 95% CI, -1.3–4.9 per 1,000). Time-to-contralateral breast cancer curves revealed a 37.5% lower relative risk with letrozole that was not statistically significant (HR, 0.63; 95% CI, 0.18–2.21; p = .12). Data on patient outcomes after unblinding of the study are presently being evaluated. Based on the results of the MA.17 trial, letrozole is now approved by the U.S. FDA as extended adjuvant therapy after 5 years of tamoxifen.
Another small trial conducted by the Austrian Breastand Colorectal Cancer Study Group (ABCSG), trial ABCSG-6a, examined the extension of adjuvant therapy, demonstrating longer event-free survival in women receiving 3 years of anastrozole versus no therapy following 5 years of tamoxifen with or without aminoglutethamide [27].
The IES was a double-blind, randomized, adjuvant sequence trial comparing 5 years of tamoxifen with the sequential use of tamoxifen followed by exemestane for a total treatment duration of 5 years [28]. Postmenopausal patients with ER+ early breast cancer (n = 4,742) who were disease free following 2–3 years of tamoxifen were assigned to either tamoxifen or exemestane for the remainder of the 5 years. The HR for breast cancer recurrence in the exemestane group versus tamoxifen was 0.68 (95% CI, 0.56–0.82; p = .00005) with a median follow-up of 30.6 months. The estimated 3-year DFS rate was significantly higher with exemestane than with tamoxifen, with an absolute benefit of 4.7%. There was also significant superiority of exemestane in regard to distant disease (HR, 0.66; 95% CI, 0.52–0.83; p = .0004) and in the risk for contralateral breast cancer (HR, 0.44; 95% CI, 0.20–0.98; p = .04). An update at 37.4 months’ median follow-up demonstrated that switching to exemestane remained significantly superior to remaining on tamoxifen for DFS (HR, 0.73; p = .0001). No OS differences have been seen between the two groups (HR, 0.83; p = .08) [29].
In a combined analysis, the ABCSG-8 trial and German Adjuvant Breast Cancer Group (ARNO)-95 trial (n = 3,224) also demonstrated significantly better event-free survival (HR, 0.60; 95% CI, 0.44–0.81; p = .0009) for tamoxifen for 2 years followed by anastrozole for 3 years compared with tamoxifen alone for 5 years [30] at a median follow-up of 28 months. Unlike the other switching trials, the ABCSG-8 trial randomized newly diagnosed patients, rather than randomizing them at the point of switch, and data on the full 5 years of adjuvant therapy were presented in abstract form at the San Antonio Breast Cancer Symposium in December 2005 [31]. At a median follow-up of 31 months, 2,529 patients were eligible for analysis: the HR for event-free survival (events defined as local or metastatic recurrence or contralateral breast cancer) was 0.61 (p = .01).
Also at the San Antonio 2005 meeting, data on a meta-analysis of the three trials that have switched patients to an AI after 2–3 years of tamoxifen were presented [32]. That meta-analysis (n = 4006) also included the Italian trial (ITA), which was an open-label study of 426 patients with node-positive breast cancer who were switched from tamoxifen to anastrozole after 2–3 years of tamoxifen [33]. Although not as strong a result as the IES "switching trial," the results are confirmatory of the benefit of early switching to an AI from tamoxifen. The results of the meta-analysis demonstrated an HR for DFS of 0.59, (p < .0001), and for OS, an HR of 0.71 (p = .038) with a median follow-up of 30 months.
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TOLERABILITY RESULTS |
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TopLearning ObjectivesAbstractIntroductionTamoxifen as Adjuvant Therapy...AIs as Adjuvant Therapy...Tolerability ResultsSkeletal EffectsClinical Use of AIs...Resistance to AIs in...ConclusionDisclosure of Potential...References |
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summarizes predefined adverse events from the upfront trials (ATAC and BIG 1–98).
General Tolerability, Urogenital Symptoms, and Hot Flashes
From the most recently published data in 2005 from the ATAC trial, with a median follow-up of 68 months, almost all patients had completed their scheduled 5 years of therapy [23]. Withdrawals because of adverse events were significantly less common with anastrozole (344, 11.1%) than with tamoxifen (442, 14.3%; p = .0002). In the BIG 1–98 trial, more patients in the letrozole group (2,912 patients) than in the tamoxifen group (2,554 patients) reported at least one protocol-specified adverse event of any grade; similar numbers of patients (67 in the letrozole-treated group vs. 69 in the tamoxifen-treated group) experienced life-threatening or fatal protocol-specified adverse events [24]. In the IES, randomly assigned treatment was stopped early in 667 patients for reasons other than relapse or death after a median of 36.1 months from the initiation of tamoxifen therapy [28]. The rate of discontinuation of therapy was slightly higher in the exemestane arm (138 patients) than in the tamoxifen arm (121 patients) because of adverse events, and another 164 patients in the exemestane arm and 116 in the tamoxifen arm refused to continue therapy. In theMA.17 trial [25,26], there were three reported reasons for patients discontinuing protocol treatment: patient refusal (11.4 % of patients receiving letrozole and 11.1% of those receiving placebo; p = .79), toxicity (4.9% of patients receiving letrozole and 3.6% of those receiving placebo; p = .019), and "other reasons" (3.8% of patients receiving letrozole and 4.7% of those receiving placebo; p = .097). Overall mental and physical QoL was not adversely impacted by letrozole in the MA.17 trial, although there were some small differences in a number of QoL domains associated with estrogen depletion, for example, vasomotor symptoms and bodily pain [34]. In the IES, there was no significant difference between the tamoxifen group and the group that switched to exemestane after 2–3 years in endocrine symptoms, except for vaginal discharge, which was more pronounced with tamoxifen; QoL was not statistically different between the groups [35].
Treatment with anastrozole in the ATAC trial was associated with significantly lower incidences of endometrial cancer (0.2% of patients in the anastrozole arm vs. 0.8% of patients in the tamoxifen arm; p = .02), vaginal bleeding (5.4% of patients in the anastrozole arm vs. 10.2% patients in the tamoxifen arm; p < .0001), hot flashes (35.7% of patients in the anastrozole arm vs. 40.9% of patients in the tamoxifen arm; p <.0001), and vaginal discharge (3.5% of patients in the anastrozole arm vs. 13.2% of patients in the tamoxifen arm; p < .0001) [21–23]. In the BIG 1–98 trial [24], as compared with tamoxifen, letrozole was associated with a lower rate of vaginal bleeding (3.3% vs. 6.6%; p < .001), fewer endometrial biopsies (2.3% vs. 9.1%; p < .001), and fewer invasive endometrial cancers (0.1% vs. 0.3%; p = .18). Hot flashes and night sweats were also significantly less frequent in the letrozole-treated patients than in the tamoxifen-treated patients in BIG 1–98. In the IES, the frequencies of hot flashes and vaginal bleeding were similar in both arms [28]; however, there was a higher percentage of patients experiencing gynecologic symptoms in the tamoxifen arm (5.8% of patients receiving exemestane vs. 9.0% of patients receiving tamoxifen; p < .001). In the MA.17 trial, hot flashes were more common in those patients receiving letrozole (58%) than in those patients receiving placebo (54%; p = .003), with vaginal bleeding more common in patients on placebo [26].
Lipid Metabolism/Cardiovascular Disease
There have been few studies to date that include an assessment of lipid effects of the AIs, and there are conflicting results among those studies that have attempted to study this question. Although tamoxifen has some favorable influences on lipid metabolism thought to be caused by the ability of tamoxifen to act as a partial agonist in some tissues, including reducing total and low-density lipoprotein (LDL) cholesterol [36], increasing high-density lipoprotein (HDL) cholesterol levels [37–40], and lowering lipoprotein-(a) Lp-(a) levels [39], it remains uncertain as to whether this translates into a reduction in coronary artery disease (CAD). Retrospective analyses have demonstrated a reduction in CAD with tamoxifen [41–43], but this benefit was not observed in the randomized prospective NSABP-P1 prevention trial comparing tamoxifen-treated patients with patients given placebo, although many more women were in a younger and premenopausal age category than in the postmenopausal adjuvant AI trials [44].
Anastrozole has shown no significant effects on serum lipids in several small studies [45–48]. However, in the ITA trial, patients switching to anastrozole after 2 or more years of tamoxifen were found to have a higher incidence of hyper cholesterolemia than those continuing on tamoxifen, 8.1% and 2.7%, respectively [33]. A recent study of 38 post-menopausal patients with breast cancer receiving anastrozole showed significant increases in total cholesterol, LDL cholesterol, and HDL cholesterol, as well as apolipoprotein (apo)-A1, apo-B, and Lp-(a) [49]. In the ATAC trial, there was no statistically significant difference in ischemic cardiovascular events (4.1% of patients receiving anastrozole vs. 3.4% receiving tamoxifen; p = .1) [23]. There was no difference in the rates of myocardial infarction in the ABCSG-8/ARNO-95 study [30].
For letrozole, increases in total cholesterol, LDL cholesterol, and apo-B and serum-lipid risk ratios for CAD were found in some studies [50, 51] but not others [52]. The MA.17 trial showed no significant difference in cardiovascular disease (5.8% of patients receiving letrozole and 5.6% of patients receiving placebo; p = .76) [26]. There were no reports of drug-related hypercholesterolemia. MA.17L is a substudy of the MA.17 trial that measured serum lipid parameters in 347 women [53]. Letrozole, after at least 5 years of tamoxifen therapy, did not significantly change serum cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, or Lp-(a). The BIG 1–98 trial studied changes in cholesterol values: the median changes in cholesterol values from baseline to 6, 12, and 24 months were 0%, 0%, and –1.8% in the letrozole group and –12.0%, –13.5%, and –14.1% in the tamoxifen group, respectively[24]. Hypercho-lesterolemia was reported at least once during treatment in a total of 43.6% (grade 1 in 35.1%) of patients in the letrozole group and 19.2% (grade 1 in 17.3%) of patients in the tamoxifen group. This low-grade hypercholesterolemia found in patients on letrozole, but not tamoxifen, is likely related to the cholesterol-lowering effect of tamoxifen [36]. More women in the letrozole group had grade 3, 4, or 5 cardiac events (2.1% vs. 1.1%; p < .001) [24]. This finding may be a result of a cardio protective effect of tamoxifen, but nonetheless, the potential for adverse cardiovascular events needs continued close and careful follow-up and monitoring.
It is possible that as a steroidal AI, exemestane may have favorable effects on serum lipid profiles compared with the other AIs. Exemestane reversed the increase in LDL cholesterol and total cholesterol seen in ovariectomized Sprague-Dawley rats [54]. In a small European Organization for Research and Treatment of Cancer (EORTC) study of patients with metastatic breast cancer, exemestane had no adverse effects on total cholesterol, HDL cholesterol, apo-A1, apo-B, or Lp-(a) levels [55]. In that same study, exemestane decreased (whereas tamoxifen increased) triglyceride levels. In the TEAM trial, which is comparing tamoxifen with exemestane as initial therapy, baseline lipid levels were compared with levels at 3 and 6 months of treatment in 37 patients [56]. Exemestane had a nonsignificant trend to increase LDL cholesterol at 3 and 6 months, but reduced triglyceride levels at both time points, while stabilizing total cholesterol and HDL cholesterol at 6 months. In a study of postmenopausal women with early breast cancer who were randomly assigned to exemestane or placebo for 2 years [57], the lipid profiles were very similar, with the exception of a modest reduction in HDL cholesterol (p < .001) and apo-A1 (p = .004) in the exemestane group. In the IES, serum lipid levels were not systematically measured. There was no significant difference in the incidence of myocardial infarction between the two treatment arms [28].
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SKELETAL EFFECTS |
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TopLearning ObjectivesAbstractIntroductionTamoxifen as Adjuvant Therapy...AIs as Adjuvant Therapy...Tolerability ResultsSkeletal EffectsClinical Use of AIs...Resistance to AIs in...ConclusionDisclosure of Potential...References |
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In the ATAC trial, tamoxifen was associated with fewer fractures and less arthralgia than was anastrozole. At the 68-month analysis, there were 340 patients with one or more fractures in the anastrozole arm versus 237 in the tamoxifen arm (OR, 1.49; 95% CI, 1.25–1.77; p < .0001) [23]. Fracture rates per 1,000 woman-years were 22.6 for anastrozole and 15.6 for tamoxifen (HR, 1.44; 95% CI, 1.21–1.68; p < .0001). The incidences of hip fracture were low and similar for anastrozole (1.2%) and tamoxifen (1.0%). In a substudy of the ATAC trial of 308 women, serial BMD decreased on anastrozole and increased modestly on tamoxifen [60].
In the BIG 1-98 trial, fractures were reported as significantly more frequent in the letrozole group than in the tamoxifen group (5.7% vs. 4.0%, respectively; p < .001), with a significantly shorter time to first fracture reported within 4 weeks after the end of treatment for the letrozole group (p < .001)[24].
Exemestane was studied in a preclinical model of ovariectomized rats; it was shown to protect against the negative effects on bone metabolism after oophorectomy [61]. A study involving healthy postmenopausal women demonstrated that exemestane given for 12 weeks caused increases in markers of bone resorption similar to the other AIs, but also increased levels of serum propeptide of type 1 collagen, a marker of bone formation, unlike the other AIs [62]. Lonning et al. [57], in a study of postmenopausal women with early breast cancer who were randomly assigned to exemestane or placebo for 2 years, showed that the mean annual rate of BMD loss was 2.7% versus 1.48% in the femoral neck (p = .024) in the exemestane and placebo arms, respectively. There was no significant difference in lumbar bone loss. Although these studies suggested that exemestane with its steroidal structure may have less adverse effects on bones, in the IES, there was a higher frequency of osteoporosis (7.4% for the exemestane group vs. 5.7% for the tamoxifen group; p = .05) and arthralgia (5.4% for the exemestane group vs. 3.6% for the tamoxifen group) [28]. Fractures were reported more frequently in the exemestane group than in the tamoxifen group, but the difference was not significant (3.1% vs. 2.3%, respectively; p = .08). The IES bone subprotocol revealed significant reductions in BMD in the first 6 months following the switch from tamoxifen to exemestane, but thereafter the decline in BMD slowed to <1% per year of therapy [63]. In the combined results of the ABCSG-8 and ARNO-95 trials, there were significantly more fractures in patients treated with anastrozole than in those treated with tamoxifen (odds ratio [OR], 2.14; 95% CI, 1.14–4.17; p = .015) [30].
Arthralgias and myalgias were significantly more common in patients on letrozole in the MA.17 study [25, 26]. Self-reported new osteoporosis was significantly different between the two arms: 209 (8.1%) patients on letrozole and 155 (6.0%) on placebo (p = .003). More patients on letrozole (137) had fractures than those on placebo (119), but the difference was not significant (p = .25) [26]. Likewise, the MA.17B bone substudy demonstrated that, at 24 months, bone loss was greater in the letrozole arm than in the placebo arm in both the hip (–4% vs. 0.7%; p = .044) and spine (–5% vs. 0.7%; p = .008) [64]. Importantly, this loss of BMD with letrozole may, in part, be offset by the benefit in BMD seen with the preceding 5 years of tamoxifen therapy. This benefit from tamoxifen was shown in the ATAC trial bone substudy [60].
Thromboembolic Events
Tamoxifen leads to an excess of thromboembolic events when compared with placebo. In the NSABP-P1 trial, pulmonary embolism was three times as common (RR, 3.01) and strokes almost twice as common among women >50 years of age receiving tamoxifen compared with younger women taking the drug (RR, 1.75) [44]. Venous thromboembolic events were more common in the tamoxifen than in the placebo arms in an analysis of all the tamoxifen prevention trials (RR, 1.9; p < .0001) [65]. Treatment with anastrozole in the ATAC trial was associated with statistically significant lower incidences of ischemic cerebrovascular and thromboembolic events compared with tamoxifen [23]. In the BIG 1–98 trial, letrozole-treated patients had fewer thromboembolic events than tamoxifen-treated patients (1.5% vs. 3.5%; p < .001) [24]. In the IES, thromboembolic events were more frequent in the tamoxifen group than in the exemestane group (2.4% vs. 1.3%, respectively; p = .08) [28]. In ABCSG-8/ARNO-95 there were significantly fewer thromboses in anastrozole-treated patients than in tamoxifen-treated patients (OR, 0.25; 95% CI, 0.04–0.92; p = .034) [30]. In the MA.17 trial, the numbers of stroke or transient ischemic attack (TIA) events were similar in the two arms (17 patients receiving letrozole and 15 receiving placebo), as were thromboembolic events (11 patients receiving letrozole and 6 receiving placebo) [26].
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CLINICAL USE OF AIS IN THE ADJUVANT SETTING WITH SPECIFIC ATTENTION TO PERIMENOPAUSAL WOMEN |
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TopLearning ObjectivesAbstractIntroductionTamoxifen as Adjuvant Therapy...AIs as Adjuvant Therapy...Tolerability ResultsSkeletal EffectsClinical Use of AIs...Resistance to AIs in...ConclusionDisclosure of Potential...References |
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). The Femara versus Anastrozole Clinical Evaluation (FACE) trial is a phase III, randomized study comparing the efficacy and safety of letrozole with those of anastrozole in postmenopausal women with node-positive breast cancer. All three third-generation AIs are being compared in a phase III, randomized trial of neoadjuvant therapy in postmenopausal women with ER+ stage II or III breast cancer. Therefore, it is possible that data will emerge from direct comparisons of the AIs on efficacy as well as side effects and toxicity. The American Society of Clinical Oncology (ASCO) Technology Assessment in 2005 recommended that the "optimal adjuvant hormonal therapy for a postmenopausal woman with receptor-positive breast cancer should include an aromatase inhibitor either as initial therapy or after treatment with tamoxifen." Of course, women with breast cancer and their physicians must weigh the risks and benefits of all therapeutic options [66]. The 2005 St. Gallen Consensus Panel felt that "recent trials support several options for postmenopausal women who require endocrine therapy, while lacking evidence to choose among them: (i) an aromatase inhibitor (anastrozole, letrozole) alone for 5 years; (ii) tamoxifen for 2–3 years followed by an aromatase inhibitor (exemestane, anastrozole) to complete 5 years of therapy; or (iii) switch to an aromatase inhibitor (letrozole) after completing 5 years of tamoxifen; (iv) finally, selected patients at low risk or with co-morbid musculo-skeletal or cardiovascular risk factors may be considered suitable for tamoxifen alone, and this may be the only option based on economic grounds in many cases" [67].
Certain select issues are important to consider when assessing an individual patient for treatment with an AI. For any woman with a contraindication to tamoxifen, or for women who have previously had therapy with a selective estrogen receptor modulator (SERM), that is, tamoxifen or raloxifene, for chemoprevention or osteoporosis, an AI should be considered for upfront therapy. For others, the question of treatment with an AI upfront versus a planned crossover to an AI remains unclear at this time [68, 69], and either approach is reasonable based on the present data. An AI upfront may be favorable in node-positive patients based on the elevated annual hazard rate for recurrence in the initial 2–3 years after diagnosis. When reviewing the toxicity data as a whole, the general statement can be made that thromboembolic events and uterine abnormalities are fewer with AIs than with tamoxifen, and there is a higher incidence of osteoporosis and/or fractures in women receiving AIs. Bone substudies are ongoing, and updated analyses will help address this issue. Furthermore, AI-associated bone loss may be prevented and treated through early detection and therapy for osteoporosis [70]. The ASCO bisphophonate guidelines identify women receiving an AI to be at high risk for osteoporosis and recommend a baseline BMD study with interventions based on this test [71].
Questions have arisen regarding whether specific subsets of patients should receive treatment with an AI upfront rather than tamoxifen. A retrospective subgroup analysis from the ATAC trial suggested that women with ER+ PR– tumors may derive greater benefit from initial therapy with an AI [72]. This same observation was not made in a subgroup analysis from the BIG 1–98 trial. That trial centrally confirmed the majority of the ER and PR markers, whereas the ATAC trial did not. Data that support a differential benefit in patients with PR– tumors include the findings that patients with such tumors are likely to have HER-1-positive (EGFR) or HER-2-positive breast cancer, positive nodes, high rates of proliferation and aneuploidy, and lower median levels of ERs [73]. Furthermore, patients with breast cancer overexpressing HER-2 may have a superior response to AIs, with supporting clinical data for this from three small, randomized, neoadjuvant trials comparing tamoxifen with AIs [74–76]. One hypothesis is that the lower efficacy of tamoxifen in HER-2-positive tumors may be related to tumors that are PR–: laboratory data have suggested that one mechanism of loss of PR expression is high growth factor receptor signaling, which, via specific sites in the PR promoter, can downregulate transcription of the PR gene [77, 78]. Clinically, this remains a debate, and in the ASCO guidelines "the Panel would generally recommend that HER-2 status not be considered when making choices about adjuvant hormonal therapy. It must be noted, however, that some Panel members are more inclined to recommend initial therapy with an AI in postmenopausal women with HER-2-positive tumor" [66].
Special attention should be addressed to perimenopausal women and those women who are premenopausal at diagnosis and who appear to have undergone menopause with chemotherapy. There is a lack of efficacy for AIs in these clinical situations; in fact, there is a potential for stimulation of the ovaries with reflex stimulation of gonadotropin secretion in premenopausal women. Although chemotherapy may result in amenorrhea, this does not necessarily equate with absence of ovarian function, with premenopausal levels of estradiol found in some women with chemotherapy-induced amenorrhea [79]. Letrozole, at 2.5 mg per day given on days 3–7 following a menstrual cycle, has been shown to be effective in inducing ovulation [80]. The ATAC trial allowed entry of women who were amenorrheic for fewer than 12 months if amenorrhea resulted from chemotherapy and if their follicle-stimulating hormone level was in the post-menopausal range. This number of patients was very small and caution should be used in generalizing these results to all premenopausal patients with chemotherapy-induced amenorrhea. At present, there are no data supporting the use of an AI in combination with ovarian function suppression, but several large, ongoing, randomized trials are addressing the value of AIs in premenopausal women. The Suppression of Ovarian Function Trial (SOFT) has a target accrual of 3,000 premenopausal women who either do not receive chemotherapy or who remain premenopausal after chemotherapy and who are randomly assigned to 5 years of treatment with tamoxifen, ovarian function suppression (OFS) plus tamoxifen, or OFS plus exemestane. The Tamoxifen and Exemestane Trial (TEXT) has a target accrual of 1,845 premenopausal women who are randomly assigned to 5 years of treatment with triptorelin plus tamoxifen or triptorelin plus exemestane. Premenopausal women in ABCSG Trial 12 are randomly assigned to receive 3 years of either tamoxifen or anastrozole, in combination with goserelin.
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RESISTANCE TO AIS IN BREAST CANCER THERAPY AND FUTURE DIRECTIONS |
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TopLearning ObjectivesAbstractIntroductionTamoxifen as Adjuvant Therapy...AIs as Adjuvant Therapy...Tolerability ResultsSkeletal EffectsClinical Use of AIs...Resistance to AIs in...ConclusionDisclosure of Potential...References |
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). MCF-7 cell derivatives that were developed in the laboratory by maintaining the culture in limited concentrations of estrogen—such as long-term estrogen deprivation (LTED) cells—are capable of growing in the presence of a 10,000 times lower concentration of estrogen than that required to support the growth of the original culture [81–83]. Several signal transducer proteins involved in nongenomic estrogen actions (e.g., Shc, Grb2, Sos) are either over expressed or constitutively activated in LTED cells [84], contributing to the enhanced estrogen sensitivity of these cells. The interaction of ER-
with these proteins leads to activation of mitogen-activated protein kinase. Further effects are mediated via the insulin-like growth factor (IGF)-1 receptor and EGFR, leading to activation of the phosphatidylinositol 3'kinase and mammalian target of rapamycin (mTOR) pathways. These signals then converge on downstream effectors, resulting in cell proliferation [85]. This leads to the hypothesis that if receptor crosstalk functions in tumors in patients, combining ER-targeted therapy with growth factor inhibitors or their downstream targets may increase their effectiveness and prevent the emergence of cells resistant to endocrine therapy. Studies with such combinations are already under way or planned, including such combinations as AIs with growth factor inhibitors (e.g., trastuzumab, gefitinib, lapatinib, IGF inhibitors), farnesyl-transferase inhibitors (tipifarnib, lonafarnib), and mTOR inhibitors (RAD001, CCI-779). It is also important to recognize that ER signaling remains an integral part of the mechanisms that drive cell proliferation, and therefore there is also much interest in evaluating the pure antiestrogen fulvestrant in combination with AIs. Preclinical data suggest that both the background estradiol levels together with the level of ER activation in resistant versus sensitive cells may be critical to the ability of fulvestrant to have growth-inhibitory effects [86, 87]. Several clinical trials combining fulvestrant with an AI are under way in patients with metastatic breast cancer, and a neoadjuvant study is also examining the combination of fulvestrant and anastrozole versus anastrozole alone. The efficacy of the AIs in reducing contralateral breast cancers sets the stage for chemoprevention trials with AIs [88]. One such study, NCIC-CTG MAP.3, randomizes women at increased risk for breast cancer to either exemestane or placebo. Another trial, the International Breast Cancer Intervention Study-II prevention trial is comparing anastrozole with placebo in postmenopausal women at increased risk for breast cancer.
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CONCLUSION |
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DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST |
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TopLearning ObjectivesAbstractIntroductionTamoxifen as Adjuvant Therapy...AIs as Adjuvant Therapy...Tolerability ResultsSkeletal EffectsClinical Use of AIs...Resistance to AIs in...ConclusionDisclosure of Potential...References |
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