Med Oncol (2008) 25:113–124 DOI 10.1007/s12032-007-9019-x
REVIEW
Aromatase inhibitors: past, present and future in breast cancer therapy Udayan Dutta Æ Kartikeya Pant
Received: 1 October 2007 / Accepted: 9 October 2007 / Published online: 1 November 2007 Ó Humana Press Inc. 2007
Abstract Estrogen has been implicated in promoting breast cancer in a majority of women. Endocrine therapy controlling estrogen production has been the guiding principle in treating breast cancer for more than a century. A greater understanding of this disease at a molecular level has led to the development of molecules that inhibit estrogen production by inhibiting the aromatase enzyme, that is the primary source of estrogen in postmenopausal women. This review examines the evolution of aromatase inhibitor (AI) based therapies over the past three decades. The third generation aromatase inhibitors (anastrozole, letrozole and exemestane), which have been found to be extremely specific and effective in an adjuvant/neoadjuvant/extended adjuvant setting are discussed from a biochemical and clinical perspective. A comprehensive discussion of the past, present, and future of aromatase inhibitors is conducted in this review. Keywords Breast cancer Estrogen Aromatase inhibitors Tamoxifen Aminogluthetimide Anastrozole Letrozole Exemestane
U. Dutta (&) Department of Cancer Biology, University of Massachusetts Medical School, LRB 470V, 364 Plantation Street, Worcester, MA 01605, USA e-mail:
[email protected] K. Pant Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Introduction Breast cancer is currently the second most lethal disease in women and is likely to affect one out of every eight women in the United States during their lifetime. It is estimated that in the year 2006 alone, over 210,000 women would be diagnosed of breast cancer (Table 1) [1]. However, since 1990 there has been a gradual decline in the rate of breast cancer deaths at a rate of nearly 2.3% a year. Early treatment techniques focused on the surgical removal of ovaries has proved to be an effective, but not a curative treatment of breast cancer [2, 3]. The emergence of data supporting the requirement of estrogen by cancer cells for their uncontrolled growth led to the emergence of new endocrine based drug therapies [4, 5]. Recent studies have also shown that avoiding the use of hormonal supplements in postmenopausal women, greatly reduced their incidence of breast cancer [6–9]. Tamoxifen was the first drug developed to block the binding of estradiol to estrogen receptor by serving as an estrogen antagonist and was effective in controlling the growth of estrogen receptor positive cancers. Tamoxifen is the hormonal treatment of choice for pre-menopausal women, however, research suggests that tamoxifen is not quite effective for postmenopausal women [10–13]. The common known side effects of tamoxifen included endometrial cancer, blood clots, endometriosis, stroke, fertility issues along with hair and nail thinning [11, 13, 14]. This led to the development of a new class of drugs, popularly known as aromatase inhibitors (AIs). AIs specifically target estrogen production rather than estrogen receptor binding and has shown promising results in treatment of breast cancer especially in postmenopausal women [15]. The review will focus on the use of AIs in an adjuvant/neoadjuvant/extended adjuvant setting from a clinical perspective.
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Table 1 Number of cases of breast cancer diagnosed and deaths over the last decade (1997–2007) Year
Female cases diagnosed
No. of deaths
2007
178,480
40,460
2006
212,920
40,970
2005
211,240
40,410
2004
215,990
40,110
2003
211,300
40,200
2002
203,500
39,600
2001 2000
192,200 182,800
40,200 41,200
1999
175,000
43,300
1998
178,700
43,500
1997
180,200
43,900
The data was derived from American Cancer Society statistics [1]
variety and range of cytochrome P450’s functions often lead to side effects due to non-specific binding of AIs. This advocates the need for continual efforts to improve specificity of the AIs along with other desirable characteristics from a drug delivery and metabolism perspective. Further, AIs are also divided into two categories based on their structure and mechanism of action, namely, steroidal and non-steroidal inhibitors (Table 2) [16, 19]. Steroidal inhibitors are substrate analogues of the aromatase and compete with the substrate for binding to the active site. Non-steroidal inhibitors have a triazole functional group that interacts directly with the heme iron in the cytochrome P450 active site thereby inhibiting the enzyme. In the following sections we shall discuss the three generations of aromatase inhibitors and describe the important steroidal and non-steroidal AIs of every generation (Fig. 2).
Aromatase inhibitor mechanism of action First generation aromatase inhibitors Aromatase is a heme containing cytochrome P-450 enzyme that converts C19 androgens to aromatic C18 estrogenic steroids. It can be detected in high levels in and around breast tumors and is expressed in the ovaries and peripheral adipose tissues of postmenopausal women [16]. The NADPH-cytochrome P450 reductase supplies electrons to the aromatase which then converts the androstenedione and testosterone to estrone and estradiol, respectively (Fig. 1) [16, 17]. In estrogen receptor positive breast cancers, the estradiol binds to the estrogen receptor and promotes tumor growth and proliferation through wide range of signaling processes. Over the past three decades AIs have provided an important alternative to tamoxifen and are often labeled as first, second and third generation inhibitors depending on their period of discovery and application [18]. The wide Androstenedione
Among the earliest AIs, aminoglutethimide was most widely used in treating advanced breast carcinoma. It is a non-steroidal inhibitor and is the amino derivative of hypnotic glutethimide that was introduced in the US in 1960 as an anticonvulsant. It was, however, withdrawn by the FDA in 1966 due to weak anticonvulsant activity and adrenal insufficiency [20]. However, in the period from late 1960s to 1970s it was found to be effective in providing objective regression of metastases in breast cancer by inhibiting aromatase [21–25]. The combination of aminogluthetimide with corticosteroids was found to be effective against breast cancer both by inducing medical adrenalectomy and inhibiting aromatases [26–29]. Its major sideeffects included liver toxicity, inhibition of cortisol production and hypothyroidism.
Testosterone
Clinical response to aminogluthetimide as first-line endocrine treatment AROMATASE
The response of aminogluthetimide treatment in comparision to trans-sphenoidal hypophysectomy was conducted by Harvey et al. [30]. In this study, 14 patients underwent Table 2 Aromatase inhibitors—classified based on their mechanism of action
Estrone
Estrodiol
Fig. 1 Mechanism of aromatase activity
Aromatase inhibitors (AIs)
Steroidal AIs
Non-steroidal AIs
First generation
Testolactone
Aminogluthetimide
Second generation
4-hydroxyandrostenedione
Fadrazole
Third generation
Exemestane
Anastrozole Letrozole
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Fig. 2 Structure of aromatase inhibitors
Aminoglutethimide
Testololactone CH3 O
NH2 CH3
O
H
C2H5 N
O
H
O
H
O
H
Fadrazole
4-hydroxyandrostenedione O N
N CN
O OH
N
Exemestane
Letrozole
Anastrozole
O N
N
N
N N
O NC NC
CN
surgery and 21 were treated with aminogluthetimide along with corticosteroid supplements. It was observed that the aminogluthetimide treatment group exhibited partial or complete tumor regression in 47% of the cases for a median duration of 11.5 months while hypophysectomy was found to be much less effective (21% with a median duration of 4.6 months) [30]. A series of studies comparing aminogluthetimide with tamoxifen have shown that aminogluthetimide therapy has the same positive effects in terms of duration and order of response as tamoxifen. However, it was reported that tamoxifen was better tolerated and caused lower incidence of side effects, as compared to the aminogluthetimide treatment groups [28, 31, 32].
Clinical response to aminogluthetimide as second-line endocrine treatment Aminogluthetimide as a second-line treatment regimen was found to be effective in patients who had resorted to oophorectomy as a first line treatment [33]. Patients previously treated with tamoxifen (i.e., in both categories, responsive and non-responsive to tamoxifen) showed a positive response to aminogluthetimide-hydrocortisone
CN CH2
treatments. On the basis of several studies performed, it was concluded that 46% of the 91 patients who were responsive to tamoxifen and 22% of the 258 patients who were non-responsive to tamoxifen, responded favorably to aminogluthetimide treatment [34–39]. These data suggested that patients showing no response to tamoxifen might be treated with aminogluthetimide in combination with hydrocortisone as a second-line regimen.
Clinical response to aminogluthetimide in an adjuvant setting The combination of aminogluthetimide with tamoxifen has been studied with mixed results. The ABCSG trial 6 was a randomized clinical study designed to compare adjuvant tamoxifen treatment in combination with aminoglutethimide with tamoxifen alone to determine the relative efficacy of the combined approach in postmenopausal women with hormone receptor-positive breast cancer [40]. In this study patients (n = 2,021) were randomly assigned to receive tamoxifen for 5 years alone or a combination of aminogluthetimide (500 mg/day) and tamoxifen (40 mg/ day) for the first 2 years of treatment and only tamoxifen (20 mg/day) was administered for the next 3 years. No
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significant differences were observed from the point of the 5 year disease free survival in the two groups (83.6% for combination arm, 83.7% for tamoxifen only arm) [40]. The overall survival at 5 years was also similar (91.4% for combination arm, 91.2% for tamoxifen only arm). However, far more patients could not complete the combination treatment (13.7%) due to the increased sideeffects as compared to the tamoxifen alone treatment group (5.2%). An Italian cooperative study was designed to determine whether switching patients from tamoxifen to aminogluthetimide would prevent some of the relapses or deaths that we assume would occur if tamoxifen were continued [41]. The study consisted of postmenopausal breast cancer patients (n = 380) receiving adjuvant tamoxifen treatment for 3 years and randomized to either continue on tamoxifen or switch to aminogluthetimide (250 mg/day) for the remaining 2 years. At a median follow-up of 61 months, no significant differences in the disease free survival between the two groups emerged (P = 0.005), however, it was observed that in the tamoxifen only group, there were higher cases of treatment failure to distant sites such as the viscera (P = 0.02) [41].
Testololactone Testololactone has been around as a drug for breast cancer since early 1960s. It is structurally related to testosterone (therefore qualifies as a steroidal inhibitor) and could have been considered as the first aromatase inhibitor [42, 43]. However, its mechanism was not known till the late 1970s. By the time the mechanism was known, it had acquired the reputation of having a low clinical activity and faced competition from the better studied rival, aminogluthetimide [44]. There were almost no clinical studies published after its mechanism of action was known [21].
Second generation aromatase inhibitors 4-hydroxyandrostenedione (4-OHA) The promising results from the first generation AIs clinical trials heralded the beginning of the development of a new generation of aromatase inhibitors that were more potent. 4-OHA (FormestaneÓ), a steroidal inhibitor was more selective and effective as a second-line agent for the treatment of breast cancer. Overall its effectiveness and selectivity has proved superior to or as good as aminogluthetimide and also caused fewer side effects. The second-generation inhibitors are about 700 times (Table 3) more potent than their first-generation counterparts [16].
Med Oncol (2008) 25:113–124 Table 3 Effect of aromatase inhibitors on aromatase activity of human breast tumors and whole body aromatization in postmenopausal breast cancer patients Aromatase inhibitor
Aminogluthetimide Formestane (4-OHA)
In vitro inhibition IC50, nm breast tumors
In vivo inhibition of whole-body aromatization
20,000
1,000
90.6
30
250
84.8
2
82.4
Fadrozole
Oral dose
% Inhibition (mg/d)
Letrozole
2
2.5
98.9
Anastrozole
8
1
96.7
Exemestane
15
25
97.9
Data and concept are derived from [20]
Extensive data, however, is not available on them, since the next generation of AI’s quickly replaced them. 4-OHA was shown to be highly effective against estrogen receptor positive tumors, while it was extremely ineffective in patients with no prior response to endocrine therapy [45]. It was not only most effective in postmenopausal women, but also showed some promise in premenopausal women when combined with goserelin, leading to a reduction in estrogen levels [46]. It also led to further reduced levels of estradiol, estrone and estrone sulfate when combined with aminogluthetimide, however, elaborate clinical trials on the efficacy of this regimen have yet to be performed [47]. Also, the need for deep intramuscular administration led to this drug not being further developed and used in an adjuvant setting [48].
Fadrozole Fadrazole is the non-steroidal counterpart of 4-OHA in the class of second generation AIs. It is, however, not as extensively studied as 4-OHA. The few studies that were performed suggested that it was as effective as tamoxifen as a first line treatment in advanced breast cancer patients, but had fewer side effects and was better tolerated and could serve as an alternative to tamoxifen for patients predisposed to thromboembolic events [49]. Due to its lower toxicity, it was also studied as a second-line therapy and was found to have a median survival period of 22.6 months [50]. Another study compared fadrozole to megestrol acetate on postmenopausal patients (n = 683), who had already received anti-estrogen therapy. The sideeffects were mild in both treatment arms with no differences in their beneficial effects [51]. Since the third-generation AI’s quickly followed, the second-generation inhibitors did not receive much attention.
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Third generation aromatase inhibitors The third-generation AIs were developed to combat hormone sensitive breast cancer in postmenopausal patients failing tamoxifen treatment [52]. This class of therapeutics included the non-steroidal inhibitors anastrozole (ArimidexÓ) and letrozole (FemaraÓ) and the steroidal inhibitor exemestane (AromasinÓ) (Fig. 2) [53–57]. These are highly selective in their mode of aromatase inhibition in comparison to their predecessors and have minimal detrimental effects on other interrelated steroidal pathways and, thus, have proved to be extremely vital in disease-free survival and preventing relapse [58–64].
Clinical response to third generation AIs in an adjuvant/ neoadjuvant setting Anastrozole is a selective orally active medication that reduces the amount of estrogens being formed from androgens by arresting aromatase activity without affecting other important hormones necessary for the body. In order to compare the safety, efficacy, and tolerance issues of anastrozole with tamoxifen as adjuvant treatment for postmenopausal women with early-stage breast cancer, the ATAC (Arimidex, Tamoxifen, alone or in Combination) trial study was carried out (Table 4) [65]. The study consisted of randomly assigned patients being administered anastrozole alone (n = 3,125, 1 mg daily) compared with patients who were administered tamoxifen alone (n = 3,116, 20 mg daily) as the first line of therapy. A third group comprised patients who were administered both drugs in combination (n = 3,125). The combination drug
study was discontinued after earlier reports comparing tamoxifen alone and the combination therapy did not show any significant differences. The remaining patients on tamoxifen or anastrozole alone were monitored further for a period of 5 years. Overall 84% of the patients were known to be hormone receptor positive and it was seen that that anastrozole treatment-related adverse events (66%) occurred significantly less often compared to tamoxifen treatment related adverse events (77%) [65, 70, 71]. Anastrozole is tolerated better than tamoxifen indicated by the lower number of patient withdrawals as a result of drug related adverse side-effect (11% vs. 14%) especially gynaecological problems and vascular events, however arthralgia and fractures were increased. Anastrozole proved to be a better first line treatment option compared to tamoxifen with a lower recurrence rate and significantly prolonged disease free survival (hazard ratio = 0.87) [70]. It has been concluded that anastrozole and tamoxifen, both maintained or slightly improved the health related quality of life of the patient undergoing treatment. Further, anastrozole also exhibited a more favorable overall risk benefit and lower recurrence rate profile than tamoxifen [71]. The impact of AI treatment on health-related quality of life has recently been reported from the ATAC trial [72]. The anastrozole (n = 335) and tamoxifen (n = 347) groups were assessed at baseline, 3 and 6 months, and every 6 months subsequently based on the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire plus endocrine subscale (ES) data. There were differences between the anastrozole and tamoxifen treatment groups in patient-reported side effects (Table 5). Based on the first report on quality of life for over 5 years of initial adjuvant therapy, it has been concluded that anastrozole and
Table 4 Pivotal clinical trials of third generation AIs [65–69] Clinical trial
Study design
Number of patients
Median follow-up (months)
Key findings
ATAC
Anastrozole alone (1 mg daily for 5 years), tamoxifen alone (20 mg daily for 5 years) and a combination of both
9,366
47
Anastrozole better as a first line treatment option with a lower recurrence rate and prolonged disease free survival (86.9% vs. 84.5%)
BIG 1-98
Letrozole alone (2.5 mg daily for 5 years), tamoxifen alone (20 mg daily for 5 years). Sequential letrozole (2.5 mg, 2 years) and tamoxifen (20 mg, 3 years) and vice versa
8,010
26
Letrozole group had a higher disease free survival rate compared to tamoxifen group (84% vs. 81.4%)
MA-17
Tamoxifen (20 mg , 5 years) followed by letrozole (2.5 mg for 5 years), tamoxifen (20 mg, 5 years) followed by placebo (5 years)
5,187
28
Letrozole therapy after tamoxifen regimen improved disease free survival compared to the placebo group (93% vs. 87%)
IES
Tamoxifen (20 mg, 2–3 years) followed by exemestane (25 mg daily for 2 years), tamoxifen (20 mg, 2–3 years) followed by placebo
4,742
30
Sequential tamoxifen–exemestance therapy had a higher disease free survival. (91.5% vs. 86.8%)
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Table 5 Health related quality of life comparison from the ATAC trial [72] Patient reported side-effects Diarrhea
Anastrozole group (n = 335) (%) 3.1
Tamoxifen group (n = 347) (%) 1.3
Vaginal dryness
18.5
9.1
Diminished libido Dyspareunia
34.0 17.3
26.1 8.1
Dizziness
3.1
5.4
Vaginal discharge
1.2
5.2
tamoxifen had similar impacts on the health related quality of life, which was maintained or slightly improved during the treatment period for both patient groups [72]. A recent separate study based on the ATAC trial data evaluated the cost-effectiveness of anastrozole to tamoxifen from a US healthcare perspective and concluded that anastrozole is a cost-effective alternative to tamoxifen for the primary adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer [73]. Two separate phase III studies (ABCSG trial 8, ARNO 95 and the ITA) showed that shifting to anastrozole treatment after 2 years of treatment with tamoxifen is more beneficial than prolonged treatment with tamoxifen alone [74–77]. In the first study, patients were treated with tamoxifen alone (n = 1,606) for 5 years or the patients were shifted to anastrozole treatment after 2 years of tamoxifen treatment (n = 1,616). It was seen that patients who had switched to anastrozole treatment after 2 years had a reduced risk of recurrence by 40% and also had lowered side-effects. The Italian Tamoxifen Anastrozole (ITA) trial randomly assigned 225 patients under tamoxifen alone treatment and 223 patients who underwent sequential treatment [74–77]. This study showed a 65% lowered likelihood of relapse in the anastrozole–tamoxifen sequentially treated group. The Immediate Preoperative Anastrozole, Tamoxifen, or Combined With Tamoxifen (IMPACT) trial was developed to study the clinical effects of neoadjuvant tamoxifen (n = 108) or anastrozole (n = 113) alone and their combination (n = 109) daily for 12 weeks before surgery in postmenopausal women with estrogen receptor positive, invasive, and non-metastatic breast cancer [78]. Although the study did not show any statistically significant differences in the different groups in reducing tumor size, however, anastrozole alone (46%) proved superior to tamoxifen alone (22%) or the combination group (26%), in women who were diagnosed initially to be needing mastectomy and saw their tumors shrink after treatment to be able to opt for breast conserving surgery [78]. The Pre-Operative Arimidex Compared to Tamoxifen (PROACT) study was a randomized trial to compare
anastrozole with tamoxifen as a preoperative treatment of postmenopausal women with large, operable breast cancer investigating the effect of AI therapy in patients scheduled for mastectomy or with inoperable tumors [79]. In this study, hormone receptor-positive breast cancer patients received anastrozole (n = 228) or tamoxifen (n = 223) with or without chemotherapy for 12 weeks before primary surgery. Drug associated side effects were observed in both the anastrozole (20.2%) and tamoxifen (18.1%) groups. Anastrozole proved to be an effective and well-tolerated preoperative therapy, producing clinically beneficial tumor downstaging and reductions in tumor burden (43% anastrozole group versus 31% tamoxifen group) causing minimal surgical interventions in patients scheduled for mastectomy, and mastectomy in patients with previously inoperable tumors [79]. Letrozole is a highly potent and specific non-steroidal aromatase inhibitor and reduces estrogen biosynthesis by binding to the heme portion of the cytochrome P450 subunit. In vitro studies have shown that letrozole is more potent than aminoglutetheide by at least two orders of magnitude [80]. A phase II, non-randomized study reported the efficacy of letrozole as a second-line therapy for advanced breast cancer patients failing tamoxifen therapy [81]. The study showed the use of letrozole had a higher clinical benefit rate (47.0%) and an objective response rate (28.2%) with a median time to progression of 9.5 months. Patients failing first-line tamoxifen therapies are usually administered aminoglutethimide or megestrol acetate as second-line therapies. However, due to the lack of selectivity in these early generation AIs has led to letrozole being investigated as a possible alternative in the metastatic setting [81]. Letrozole treatment (2.5 mg daily) has been found to be more effective than tamoxifen in early hormone sensitive breast cancer [82]. The effectiveness of letrozole has been shown through the results of two randomized international clinical trials, namely, BIG 1-98 and MA-17 trial. The Breast International Group (BIG) 1-98 study was a randomized phase III multinational trial conducted to compare letrozole against tamoxifen in a first-line monotherapy and an adjuvant setting (Table 4) [66, 83]. The study divided the patients in four groups—patients receiving letrozole (2.5 mg daily) or tamoxifen (20 mg daily) alone for 5 years and patients sequentially receiving letrozole for 2 years followed by tamoxifen for 3 years and vice versa. The letrozole group consisted of 4,003 patients and the tamoxifen group consisted of 4,007 patients with hormone receptor positive early stage breast cancer. After the median follow-up of 26 months, the letrozole group showed a 19% lowered chance of recurrence and a 27% lowering of distant metastases [83, 84]. Some patients receiving chemotherapy after this treatment showed 30%
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lowered recurrence in letrozole group compared to the tamoxifen group. Also the letrozole group had a projected 84% disease-free survival in contrast to the 81.4% of the tamoxifen group with no difference in the overall survival in either study groups [66, 83]. Thromboembolism, endometrial cancer, and vaginal bleeding were more common in the tamoxifen group and the letrozole group exhibited a higher incidence of skeletal and cardiac events and of hypercholesterolemia. The comparison of initial tamoxifen and letrozole included all patients randomly assigned to the monotherapy arms or the sequential therapy arms making it difficult to compare with other AI studies. Recently an update of the BIG 1-98 study focusing on 5 years of monotherapy comparing letrozole with tamoxifen has come out allowing for a direct comparison with the ATAC trial [66]. This analysis is restricted to patients who were randomly assigned to the monotherapy arms (letrozole group = 2,463; tamoxifen group = 2,459). The primary end point was disease-free survival (DFS) and protocol-specified secondary end points that included overall survival and systemic DFS. At a median follow-up time of 51 months there was an 18% reduction in the risk of an event (hazard ratio = 0.82) and none of the monotherapy groups showed differential beneficial results [66]. The present BIG 1-98 analysis showed identical hazard ratios for the exploratory end point of time to recurrence with no significant difference in overall survival when compared to the previously mentioned ATAC trial [66, 70]. This analysis further supports the inclusion of an AI in the adjuvant therapy of postmenopausal women with receptor-positive early breast cancer. The MA-17 was a randomized double-blind placebo controlled trial to study the effectiveness of letrozole therapy for 5 years in postmenopausal women who were diseasefree after 5 years of tamoxifen treatment (Table 4) [67, 68]. One group of patients received letrozole (n = 2,593) and another group received a placebo (n = 2,594). The primary endpoint of this study was disease free survival and the secondary end points were overall survival, quality of life and long-term safety. Letrozole therapy after standard 5 year tamoxifen therapy significantly improved disease free survival and was 93% compared to 87% in the placebo group [67, 68]. The results for toxicity and side-effect issues were variable and not statistically different in either subgroup monitored in the study. The effect of letrozole on the quality of life was examined as part of a substudy of the parent MA-17 trial [85]. This substudy contained a placebo group (n = 1,799) or letrozole group (n = 1,813) who had prior to this had completed 5 years of tamoxifen treatment and were disease free. The results showed no detrimental effect on the patient’s quality of life compared to the placebo. In certain
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domains, letrozole use did show some improvements in the overall quality of life and lowered side-effects. Also there was no long-term safety and tolerability issues due to letrozole use and reduced estrogen synthesis. Separate substudies of the MA-17 trial focused on the serum lipid profile (MA-17L) and bone mineral density (MA-17B) [86, 87]. The purpose of MA-17L study was to measure cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and lipoprotein(a) and evaluate changes in serum lipid parameters in postmenopausal women receiving letrozole (n = 183) or placebo (n = 164) alone after adjuvant tamoxifen for early-stage breast cancer. Previous studies [86] have shown that tamoxifen has a favorable affect on lipid, resulting in significant decreases in total and LDL cholesterol serum levels and a concomitant rise in serum HDL cholesterol. The MA-17L study showed a significant improvement in disease-free survival with the use of letrozole, as extended adjuvant therapy after tamoxifen treatment [86]. There was no significant differences in serum cholesterol, HDL cholesterol, LDL cholesterol, triglycerides or Lp(a) up to 36 months among the study subgroups. These findings further supported the tolerability and safety of extended adjuvant letrozole treatment in node positive patients following standard tamoxifen therapy. Aromatase inhibition decreases estrogen levels and this may be a factor actively influencing bone strength in patients undergoing hormonal treatment. The effect of letrozole treatment on a prevalent bone rupture side-effect was carried out by measuring bone turnover markers and bone mineral density in postmenopausal women were randomly assigned as part of a substudy of the larger MA.17 trial [87]. This MA-17B substudy consisted of 122 patients receiving letrozole and 104 patients receiving placebo alone after standard adjuvant tamoxifen treatment completion. The study found that subsequent extended adjuvant letrozole treatment causes a slight increase in bone resorption and a reduction in bone mineral density in the spine and hip, as compared to the placebo subgroup. A randomized double-blind trial in postmenopausal women (n = 157) with advanced breast cancer was carried out to compare the efficacy, safety and tolerability of letrozole in comparision to fadrozole hydrochloride. Letrozole (1 mg/day) was found to have a higher overall response rate than fadrozole (1 mg twice/day) (31.2– 13.2%). Further median time of progression was 211 days for the letrozole group when compared to 113 days for the fadrozole group. Adverse drug reactions were higher for the fadrozole group (39.5%) when compared to the letrozole group (39.5%) [88]. A small randomized crossover study was conducted to compare the effects of anastrozole (1 mg daily) and
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letrozole (2.5 mg daily) on total-body aromatization and plasma estrogen levels [89]. Twelve postmenopausal women with estrogen receptor positive metastatic breast cancer in a randomized sequence were treated with anastrozole (1 mg) and letrozole (2.5 mg) for 6 weeks. The plasma levels of estrone, estradiol and estrone sulfate were determined in serum samples using dual isotopic labeling technique and analyzed using high performance liquid chromatography. Treatment with anastrozole suppressed plasma levels of estrone, estradiol and estrone sulfate by a mean of 81.0%, 84.9%, and 93.5%, respectively, whereas treatment with letrozole caused a corresponding decrease of 84.3%, 87.8% and 98.0%, respectively. This study revealed letrozole ([99.1% inhibition) to be a more potent suppressor of total-body aromatization and plasma estrogen levels compared with anastrozole (97.3%) [89]. However, the clinical significance of these slight differences between the two AIs is still unknown. Exemestane is a steroidal inhibitor of aromatase and leads to a long term decrease in plasma and urinary estrogen levels. The Intergroup Exemestane Study (IES) trial was a randomized trial carried out in postmenopausal hormone sensitive breast cancer patients after 2–3 years of tamoxifen therapy to evaluate, whether sequential treatment with exemestane was better than continuing further with tamoxifen treatment (Table 4) [69, 90, 91]. The study had the sequential treatment group (n = 2,362, 25 mg exemstane daily) and the continued tamoxifen group (n = 2,380) for a total of 5 years of treatment. The study showed that patients, who went through the sequential tamoxifen–exemstane treatment had a increased disease free survival (15%) and a lowered risk of recurrence by 24% [69]. Also the chances of distant metastases were greatly reduced in the exemestane group with significantly reduced side effects. A controlled study was conducted to study the effect on bone health in a subgroup of postmenopausal women (n = 206) participating in the IES study who were disease-free after 2–3 years of treatment with tamoxifen and were randomized to continue oral tamoxifen or exemestane to complete a total of 5 years of adjuvant endocrine therapy [92]. The primary endpoint was assessment of changes in bone-mineral density or bone turnover and the incidence of fractures. Recent results indicate that the increase in survival seen in the IES study is achieved at the expense of some bone loss and increased fracture risk [92]. The National Surgical Adjuvant Breast and Bowel Project (NSABP) developed protocol B-33, a randomized double-blind trial comparing exemestane (25 mg daily) with placebo for 5 years in an extended adjuvant setting in postmenopausal patients who have recurrence-free after completing 5 years of tamoxifen treatment (20 mg daily) [93]. The primary goal of the study was to assess the
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disease -free survival rate of switching to exemestane with secondary aims to determine whether exemestane will prolong overall survival and any related side-effects. The MA.17 trial results led to the study to be converted to unblinded at which stage all patients receiving placebo were offered exemestane. About 44% of such patients chose to switch to exemestane, while the majority of patients on the exemestane group (72%) continued with the trial. Early reports show patients with hormone receptorpositive breast cancer who received exemestane after 5 years of tamoxifen were 56% less likely to have a relapse of breast cancer than those who received placebo (P = 0.004). Disease-free survival was improved by 32% (P = 0.07) after a medium follow up of 2.5 years with acceptable toxicity in the adjuvant setting [93, 94]. An interesting feature regarding the dosage over the three generations of AI’s has been that aminogluthetimide was administered in doses of several 100 mg almost a gram while the second generations AI’s were administered at a dosage of a few milligrams a day, while the third generation AI’s are administered at a dose of a milligram a day.
Currently undergoing aromatase inhibitor based clinical trials Aromatase inhibitor therapy is currently popular and effective in treating postmenopausal hormone receptor positive breast cancer [19, 95, 96]. However, there is still not a single-standard solution to combat this disease completely, so it is still in the hands of healthcare professionals who need to make decisions on a case-by-case basis as to the kind of drug regimen the patient needs to follow to overcome this disease. Needless to say the discovery and development of more potent drugs and therapies need to continue together with the undergoing clinical trials. In order to make a more informed decision, the search still goes on through several clinical trials, the best combination, and timing of all these available for third-generation AIs in a neoadjuvant, adjuvant or an extended adjuvant setting for maximal benefit to the patients. The efficacy of these third-generation AIs in comparison to each other is still not known. A phase III comparison trial of letrozole to anastrozole in the adjuvant treatment of postmenopausal women with hormone receptor and nodepositive breast cancer is being carried out for a period of 5 years and the disease survival status in these patients (n = 4,000) will be evaluated [97]. Another phase III randomized adjuvant double-blind study in estrogen receptorpositive breast cancer patients (n = 6,840) is to compare the event-free survival of postmenopausal women, when treated with exemestane or anastrozole for 6 years after undergoing surgery for primary breast cancer [98]. A
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Multi-Center Randomized Clinical Trial correlating the effects of 24 months of exemestane or letrozole to identify which women (n = 160) are more likely to have certain benefits or side effects of exemestane or letrozole by studying their genes and following the medication’s effects on the patients body [99]. A separate neoadjuvant trial is evaluating the effectiveness of use of exemestane (25 mg), letrozole (2.5 mg), or anastrozole (1 mg) daily for 16– 18 weeks in treating postmenopausal women (n = 375) who are undergoing surgery for stage II/III breast cancer [100]. The results will be used to perform a future study that will compare neoadjuvant aromatase inhibitor treatment with neoadjuvant chemotherapy. A phase IV trial study is being carried out to determine changes in baseline breast density in postmenopausal women with hormonereceptor positive primary breast cancer taking letrozole or exemestane for a period of 24 months and to correlate the observed changes with wild type or variant aromatase [101]. It is also speculated that the use of AIs as a combination drug might prove to be more beneficial to a diverse group of breast cancer patients and several clinical trials are being conducted to address this issue and evaluate AI therapy benefits in this complementary role. The study of anastrozole and radiotherapy sequencing (STARS) trial is being conducted to compare the use of anastrozole before and during radiotherapy in contrast to its use after irradiation [102]. In patients with overexpressing Her-2 (member of the epidermal growth factor receptor (EGFR) family and is notable for its role in the pathogenesis of breast cancer and as a target of treatment) along with estrogen receptor and/ or progesterone receptor positive metastatic breast cancer, a phase IV trial is investigating the effect of the combination of letrozole with trastuzumab [103]. Also the effect of a EGFR/erbB2 inhibitor GW572016 with or without letrozole in treating stage IV breast cancer patients is being investigated [104]. Studies are underway to evaluate the efficacy of aromatase inhibitor therapy in combination with other known types of drugs believed to be effective against breast cancer like celecoxib (cox-2 inhibitor), sorafenib (PDGF and VEGF inhibitor), gefitinib (EGFR inhibitor), and everolimus (mTOR inhibitor). Several studies are also being carried out to alleviate the painful side-effects of AI therapy. A phase III clinical trial concluded after 3 years of study that zoledronic acid (bisphosphonate) could prevent treatment-induced bone loss in premenopausal women undergoing total estrogen suppression after surgery to remove their hormonereceptor-positive tumors [105]. However, the long-term effects of zoledronic acid are still not known. A phase IV study aims to determine whether the joint pains experienced by patients undergoing AI therapy is associated with more defects in their cartilage, compared to patients
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not receiving this therapy using magnetic resonance imaging (MRI) and assessing changes in cartilage volume for 2 years [106]. The use of an oral bisphosphonate (alendronate) in preventing bone loss in postmenopausal women with early breast cancer who are receiving anastrozole therapy is currently under evaluation [107]. These studies are believed to improve our understanding of the various options available in the treatment of breast cancer.
Conclusion Recent data from national healthcare agencies has shown significant success in improving the survival rates among breast cancer patients. This advancement is attributed to a more patient selective drug regimen based on the diverse clinical result data that are slowly becoming available to oncologists and helping them in better understanding various cancer phenotypes. The need for unraveling the intricate disease mechanisms and developing more potent therapeutics cannot be undermined. The history of drug development in the field of AI’s is an example of how improvements in the design of one type of drug can bring about an entire class of new highly effective drugs. The lessons from this success could be emulated in other therapies like herceptin and tamoxifen. The use of AIs has been very successful in combating hormone sensitive breast cancer in postmenopausal women [19, 95, 96, 108–110]. However, the risk of these cancers developing resistance to the available therapeutics cannot be ignored. In order to address this issue a comprehensive genomic, proteomic and metabolic understanding of these diverse cancer phenotypes need to be developed. Also, knowledge of the crystal structures of the key enzymes and their conformations during drug metabolism would definitely aid in furthering the development for the next generation of AI’s.
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