The Oncologist, Vol. 11, No. 7, 718-731, July 2006; doi:10.1634/theoncologist.11-7-718 © 2006 AlphaMed Press
Adjuvant Hormonal Therapy in Peri- and Postmenopausal Breast CancerMassachusetts 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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Tamoxifen has been the mainstay of endocrine treatment for early-stage breast cancer in both premenopausal and postmenopausal women for many years. Since 2001, the results of several large, randomized, clinical trials have provided evidence that aromatase inhibitor (AI) therapy, either upfront or in sequence after tamoxifen, improves disease-free survival and, in certain patients, overall survival for postmenopausal patients with hormone receptor-positive breast cancer. Thus far, with relatively short-term follow-up, AIs have been generally safe and well tolerated among the population of patients treated in these adjuvant trials. However, important side effects such as musculoskeletal and bone-related problems, including the risk for osteoporosis and fractures, remain of concern and warrant continued monitoring and follow-up. Several questions regarding the appropriate AI to use and the timing of AI therapy remain unresolved, and ongoing studies will help address these issues. Caution is warranted in the use of AIs in perimenopausal women, including those that develop chemotherapy-induced amenorrhea, and clinical evidence supports the role for AI use in postmenopausal women only. Areas of active investigation include the mechanisms of resistance to endocrine therapy with tamoxifen and AIs and clinical strategies to overcome this resistance.
Over the past 5 years, there has been remarkable progress in delineating the role of aromatase inhibitors (AIs) for the treatment of postmenopausal breast cancer. Modest gains in progression-free survival in the metastatic setting with AI therapy versus tamoxifen have translated into substantial gains in the adjuvant treatment of postmenopausal breast cancer. Several large, randomized trials with AIs have been completed or are ongoing, including among them more than 30,000 women with early-stage breast cancer, documenting the significant impact that these drugs are making on the risk for recurrence of breast cancer. As a result, there is increasing and widespread use of AI therapy for the treatment of early-stage endocrine-responsive breast cancer.
Targeted hormonal therapy with tamoxifen has saved thousands of lives and has been the most widely prescribed treatment for early-stage breast cancer. Tamoxifens role in the adjuvant treatment of breast cancer was summarized in the recent Early Breast Cancer Trialists Collaborative Group (EBCTCG) 15-year update [1]. In women with estrogen receptor-positive (ER+) disease, 5 years of tamoxifen reduced the annual breast cancer death rate by 31%, irrespective of age, administration of adjuvant chemotherapy, progesterone receptor (PR) status, or other tumor characteristics [1]. 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 tamoxifens 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.
With this unmet clinical need for improvement in the adjuvant treatment of hormone receptor-positive breast cancer, combined with knowledge of the mechanisms of resistance to tamoxifen, the principle question asked in the design of the adjuvant trials with AIs was whether AIs could either substitute for tamoxifen or add to tamoxifen to improve efficacy with acceptable toxicity. AIs act by blocking the aromatase enzyme in the final step of estrogen synthesis, thus lowering circulating estrogen levels and depriving the ER of its substrate. AIs, unlike tamoxifen, lack partial agonist activity of the ER. The suppression of circulating estrogen is profound, approximately 95%–98% with all the third-generation AIs [16–18]. AIs are classified by their mechanism of action into steroidal (irreversible, type I) and nonsteroidal (reversible, type II) inhibitors [19, 20]. The AIs in clinical use today include the third-generation steroidal AI exemestane and the nonsteroidal AIs anastrozole and letrozole. Remarkably, more than 30,000 postmenopausal women are represented in the several large, randomized studies that compare AIs with tamoxifen, either as upfront therapy or as extended adjuvant therapy after tamoxifen or in sequence (Fig. 2
Upfront 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 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.
An important consideration in clinical decision making regarding the use of an AI is the potential impact of the inhibition of estrogen synthesis on quality of life (QoL) and the potential adverse impact on bone and lipid metabolism, urogenital function, and arterial and venous thromboembolic events. It is important to keep in mind the design of the adjuvant trials: that is, side effects and toxicity are assessed as a comparison with tamoxifen or after a patient has had exposure to tamoxifen for 2 to as many as 5 years. The MA.17 trial is unique in its evaluation of an AI compared with placebo, although these patients would have had exposure to approximately 5 years of prior tamoxifen therapy that may impact the results as well, one obvious bias being that women who developed significant side effects from tamoxifen may not have remained on therapy and become eligible for letrozole subsequently. The following sections address these issues. Table 2
General Tolerability, Urogenital Symptoms, and Hot Flashes 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 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].
NSABP-P1 is the only prospective trial that has measured the effect of tamoxifen on bone fractures versus placebo [44]. It showed a reduction in the risk for long bone and symptomatic vertebral fractures of borderline statistical significance (risk ratio [RR], 0.81; 95% CI, 0.63–1.05). Studies have shown that tamoxifen preserves bone mineral density (BMD) in postmenopausal breast cancer patients [58, 59]. 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
Overall, the data from these large adjuvant trials strongly favor incorporating an AI as adjuvant therapy following a careful discussion with breast cancer patients regarding the benefits and risks of these drugs; however, it is important to keep in mind that several clinical questions remain unanswered. These include the optimal duration of treatment with an AI, whether tamoxifen or an AI should be given first, whether sequential treatment is optimal, which AI is superior, whether an AI is beneficial for a premenopausal woman after ovarian ablation, and, finally, whether tamoxifen alone is suitable for certain patients. Current clinical trials are addressing some of these questions. Ongoing analyses of the BIG 1–98 trial will address the important comparison of the sequence of tamoxifen followed by letrozole with letrozole followed by tamoxifen. MA.17R is an extension of the MA.17 trial that is randomly assigning patients to a further 5 years of either letrozole or placebo. The results of that study will allow a better determination of the optimal duration of treatment for efficacy as well as long-term toxicity for patients treated beyond 10 years from initial diagnosis. No direct comparisons of the individual AIs in the adjuvant setting have been made to date. A large phase III randomized adjuvant trial, MA.27, is comparing anastrozole with exemestane as upfront therapy (Fig. 1 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.
The molecular basis of acquired resistance of breast cancer to aromatase inhibition has not been established. Data have demonstrated that various growth factor pathways and oncogenes involved in the signal transduction cascade become activated and used by breast cancer cells to bypass normal endocrine responsiveness. The key pathways include cell surface-based growth factor receptors such as EGFR and HER-2, intracellular kinase cascades, and proteins that regulate the cell cycle and transcription of genes involved in cell proliferation. ER signaling remains critically important as cells adapt and become hypersensitive to low levels of estrogen. Several independent sources suggest that, in the presence of chronic estrogen deprivation, resistant cells become exquisitely hypersensitive to estrogen (Fig. 1 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.
Great strides have been made in recent years in the treatment of hormone-responsive postmenopausal breast cancer with AIs. The recent adjuvant trials have provided evidence that AIs are both safe and effective in the short term. Furthermore, our recent improved understanding of the molecular basis for resistance to endocrine therapy with tamoxifen or AIs has led to many trials already completed or under way that study combinations of SERMs and AIs with signal transduction pathway inhibitors that will potentially lead to improved efficacy of these drugs in certain patients. We are also hopeful that molecular characterization of individual tumors will assist in determining a tumors sensitivity to various agents. Longer follow-up from the adjuvant studies of AIs will allow us to provide our patients with better knowledge of the benefits and long-term risks of AIs. The outlook is promising that new therapeutic approaches including AIs will lead to further improvement in survival among postmenopausal women with breast cancer.
P.D.R. has received honoraria from Novartis and support from Pfizer. P.E.G. has received speaker honoraria and serves on the advisory boards for AstraZeneca, Novartis, and Pfizer.
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