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First Published Online August 11, 2008
The Oncologist, Vol. 13, No. 8, 829-837, August 2008; doi:10.1634/theoncologist.2008-0055
© 2008 AlphaMed Press

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Breast Cancer

Aromatase Inhibitors: Are There Differences Between Steroidal and Nonsteroidal Aromatase Inhibitors and Do They Matter?

William R. Millera, John Bartletta, Angela M. H. Brodieb, Robert W. Brueggemeierc, Enrico di Salled, Per Eystein Lønninge, Antonio Llombartf, Nicolai Maassg, Thierry Maudelondeh, Hironobu Sasanoi, Paul E. Gossj

aUniversity of Edinburgh, Edinburgh, UK; bUniversity of Maryland School of Medicine, Baltimore, Maryland, USA; cThe Ohio State University, Columbus, Ohio, USA; dPfizer Italia s.r.l., Milan, Italy; eSection of Oncology, Institute of Medicine, University of Bergen, Bergen, Norway; fHospital Universitari Arnau de Vilanova, Lleida, Spain; gUniversity of Kiel, Kiel, Germany; hUniversity Montpellier 1, Centre Hospitalier Universitaire, Montpellier, France; iTohoku University School of Medicine, Sendai, Miyagi, Japan; jHarvard Medical School, Boston, Massachusetts, USA

Key Words. Aromatase inhibitor • Exemestane • Letrozole • Anastrozole • Mechanism of action

Correspondence: William R. Miller, D.Sc., Ph.D., Breast Unit, Paderewski Building, Western General Hospital, Edinburgh EH4 2XU, United Kingdom. Telephone: 0131-537-2501/5; Fax: 0131-537-2449; e-mail: wmiller{at}staffmail.ed.ac.uk

Received March 6, 2008; accepted for publication June 13, 2008; first published online in THE ONCOLOGIST Express on August 11, 2008.

Disclosure: W.R.M. discloses that this article discusses letrozole (Novartis), anastrozole (AstraZeneca), and exemestane (Pfizer) for validation of mechanism of action. He has also been on the advisory board for Pfizer and received speaker's honoraria. J.B. has received honoraria and research funding from Pfizer (exemestane). A.M.H.B. has received honoraria and research support from AstraZeneca (anastrozole research). R.W.B. discloses that this article discusses exemestane (Pfizer), anastrozole (AstraZeneca), and letrozole (Novartis) for use in breast cancer therapy. He also received an honorarium for participating in an expert panel meeting from Pfizer/CC Ford Healthcare. E.d.S. is an employee and has stock options in Pfizer (exemestane). P.E.L. has received speaker's honoraria from Novartis, AstraZeneca, and Pfizer. A.L. discloses no conflict of interest. N.M. discloses that the article discusses exemestane (Pfizer), anastrozole (AstraZeneca), and letrozole (Novartis) for breast cancer treatment, and he has been on an advisory board and received honoraria from Pfizer (exemestane). T.M. has research funding from Novartis (letrozole) and has received a consulting fee from Pfizer (exemestane). H.S. has research funding and has received an honorarium from Pfizer (exemestane). P.E.G. discloses that this article discusses letrozole (Novartis), anastrozole (AstraZeneca), and exemestane (Pfizer) for validation of mechanism of action. He also discloses that the article discusses aromatase inhibitors for prevention (Novartis, AstraZeneca, Pfizer), and that he has received speaker's honoraria from Novartis, AstraZeneca, and Pfizer. The content of this manuscript has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from any commercial bias; they have disclosed no financial relationships relevant to this content.


   ABSTRACT
Top
 Abstract
Introduction
 Interactions with Aromatase
 Androgenic Versus Nonandrogenic...
 Clinical Implications
 Summary
 Conclusions
 Author Contributions
 References
 
Aromatase inhibitors (AIs) are approved for use in both early- and advanced-stage breast cancer in postmenopausal women. Although the currently approved "third-generation" AIs all powerfully inhibit estrogen synthesis, they may be subdivided into steroidal and nonsteroidal inhibitors, which interact with the aromatase enzyme differently. Nonsteroidal AIs bind noncovalently and reversibly to the aromatase protein, whereas steroidal AIs may bind covalently and irreversibly to the aromatase enzyme. The steroidal AI exemestane may exert androgenic effects, but the clinical relevance of this has yet to be determined. Switching between steroidal and nonsteroidal AIs produces modest additional clinical benefits, suggesting partial noncrossresistance between the classes of inhibitor. In these circumstances, the response rates to the second AI have generally been low; additional research is needed regarding the optimal sequence of AIs. To date, clinical studies suggest that combining an estrogen-receptor blocker with a nonsteroidal AI does not improve efficacy, while combination with a steroidal AI has not been evaluated. Results from head-to-head trials comparing steroidal and nonsteroidal AIs will determine whether meaningful clinical differences in efficacy or adverse events exist between the classes of AI. This review summarizes the available evidence regarding known differences and evaluates their potential clinical impact.


   INTRODUCTION
Top
 Abstract
 Introduction
Interactions with Aromatase
 Androgenic Versus Nonandrogenic...
 Clinical Implications
 Summary
 Conclusions
 Author Contributions
 References
 
Breast cancer is the most common cancer among women worldwide [1]. Most breast cancers in postmenopausal women are estrogen receptor positive (ER+) [2, 3]. In this population, endocrine therapies designed to prevent estrogen-driven proliferation can induce tumor regression. There are currently two major treatment modalities to prevent the effects of estrogen: "antiestrogens," which target and antagonize ER-mediated action, and aromatase inhibitors (AIs), which inhibit estrogen biosynthesis. Aromatase is the final enzymatic step in catalyzing the biosynthesis of estrogens (Fig. 1), thereby making the enzyme an attractive therapeutic target.


Figure 1
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  		Figure 1. The estrogen synthesis pathway.

 
The evolution of AIs has seen the transition from prototype agents that were either not particularly potent or selective to third-generation drugs that are considerably more potent and specific. Third-generation inhibitors represent a significant advance in the therapy of ER+ breast cancer in postmenopausal women, and are approved as treatments for both early- and late-stage ER+ breast cancer [4–6].

AIs can be classified either as steroidal (type I inhibitors) or nonsteroidal (type II inhibitors), based on their chemical structure. In terms of the current inhibitors, anastrozole and letrozole are nonsteroidal, whereas exemestane is a steroidal inhibitor.

All AIs are similar in that they inhibit estrogen synthesis by blocking aromatase activity, thereby reducing endogenously synthesized estrogen. However, there are distinct differences among them. These are either class-independent differences in terms of potency [7] or class-specific differences in terms of the mechanism of binding to aromatase. There may also be clinically relevant differences among AIs related to the androgenic properties of steroidal AIs. This review summarizes the available evidence relating to class differences and evaluates how these may translate into clinical effects.


   INTERACTIONS WITH AROMATASE
Top
 Abstract
 Introduction
 Interactions with Aromatase
Androgenic Versus Nonandrogenic...
 Clinical Implications
 Summary
 Conclusions
 Author Contributions
 References
 
Aromatase is a member of the cytochrome P450 (CYP)19 family of enzymes [8–10]. Nonsteroidal type II AIs, such as anastrozole and letrozole, interact noncovalently with the heme moiety of aromatase and occupy its substrate-binding site, thereby preventing binding of androgens to the catalytic site [11] (Fig. 2). This antagonism is reversible, and the type II AIs can be competitively displaced from the active site by endogenous substrate. In contrast, the steroidal type I inhibitor exemestane is an analogue of the natural aromatase substrate androstenedione. Exemestane is recognized by the active site of aromatase as an alternate substrate [8, 10, 12] (Fig. 2). However, it appears to be converted by aromatase into a reactive intermediate that binds irreversibly and covalently to the substrate-binding site of aromatase, permanently inactivating the enzyme [12]. Irreversible AIs are also known as inactivators or "suicide" inhibitors because aromatase is inactivated because of its own mechanism of action [12].


Figure 2
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  		Figure 2. Schematic representation of the binding of (A) steroidal (type I [exemestane]) and (B) nonsteroidal (type II [letrozole]) aromatase inhibitors to the aromatase enzyme.

 
Differences in binding between nonsteroidal and steroidal AIs lead to divergent effects on aromatase in experimental systems. In the MCF-7aro breast cancer cell line, which has been transfected with aromatase, exemestane destabilizes the enzyme so that aromatase protein exposed to exemestane is degraded at a greater rate by proteosomic enzymes than the nonexposed enzyme [13]. In contrast, nonsteroidal inhibitors may increase aromatase protein levels because they stabilize the structure of the enzyme [13] and/or induce transcription of aromatase mRNA [14, 15]. The consequence of this upregulation, together with the reversible nature of type II inhibitors, is that it is possible to demonstrate increases in enzyme activity following exposure to type II inhibitors. Thus, both Miller and Dixon (using human breast fibroblasts) [16] and Soudon (using the choriocarcinoma cell line JEG-3) [17] have shown that exposure to type II inhibitors followed by assaying in the absence of inhibitor results in an increase in aromatase activity, an effect not seen with exemestane. This is consistent with data from ex vivo assays for aromatase activity following neoadjuvant treatment with aminoglutethimide [18]; aminoglutethimide is a potent inducer of multiple CYP enzymes [19].

Theoretically, irreversible steroidal AIs such as exemestane are expected to have a longer duration of inhibition than reversible AIs because estrogen synthesis can only resume following de novo synthesis of aromatase. However, based on in vivo data, this occurs relatively quickly (i.e., within 1–2 days) [20]. In addition, the pharmacokinetic properties of each specific AI affect the duration of estrogen suppression. In any event, the clinical scheduling for exemestane, as with the nonsteroidal inhibitors, is daily dosing [6]. The inductive/stabilizing effects of nonsteroidal AIs on aromatase protein do not seem to affect their ability to lower estrogen levels or whole body aromatase activity in the short term [21, 22]. When given daily in therapeutic doses, both letrozole and anastrozole profoundly inhibit aromatase activity and effectively suppress estrogen levels in postmenopausal women at 3 months. However, it is possible (although currently unproven) that prolonged treatment with nonsteroidal AIs could result in high levels of aromatase and resumption of estrogen biosynthesis, which may contribute to the development of resistance. This hypothesis could be tested by collecting tissues from patients recurring on nonsteroidal AIs and measuring levels of aromatase mRNA, protein, and activity. Although there are few data exploring the long-term endocrine effects of an AI, a study by Dowsett et al. [23] reported that plasma estrone levels of aminoglutethimide-treated patients increased slightly shortly before relapse, which is consistent with the concept.

Although aromatase in normal tissues is differentially regulated through a variety of promoters [24], there appears to be only one human aromatase gene and a single protein translate. However, it is possible that in tumors there may be mutations that could affect aromatase protein structure or sensitivity to inhibitors. In this respect, structural functional studies on aromatase have produced proteins that appear resistant to a steroidal AI (formestane) while maintaining sensitivity to nonsteroidal AIs [25]. Such a phenotype has been reported in some breast cancers, for which causative mutations have not been identified [26]. The possibility exists, therefore, that aromatase in individual breast cancers may be more susceptible to one class of AI than another. This may be important because intratumoral aromatase may be responsible for the higher levels of estrogen generally seen in postmenopausal tumor tissue, relative to those in the circulation [16, 27–29].


   ANDROGENIC VERSUS NONANDROGENIC PROPERTIES
Top
 Abstract
 Introduction
 Interactions with Aromatase
 Androgenic Versus Nonandrogenic...
Clinical Implications
 Summary
 Conclusions
 Author Contributions
 References
 
The androgenic structure of type I steroidal AIs may give rise to hormonal effects apart from the decrease in estrogen production caused by inhibition of aromatase. The androgenic properties of exemestane make it distinct from the nonsteroidal AIs letrozole and anastrozole. Exemestane is structurally related to androstenedione. The principal metabolite of exemestane, 17-hydroexemestane (17β-hydroxy-6-methylenandrosta-1,4-diene-3,17-dione), binds with high affinity to the androgen receptor (AR) (Table 1) [6, 30, 31]. When exemestane is given to postmenopausal women at the approved dose of 25 mg daily, the circulating levels of 17-hydroexemestane are approximately 15% that of unchanged exemestane [32].


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  		Table 1. Relative binding affinity (RBA) of exemestane and 17-hydroexemestane to the androgen receptor (AR) as compared with the specific ligand 5{alpha}-dihydrotestosterone (DHT) or metribolone (R1881)

 
Because >60% of breast tumors express ARs, a role for androgens in the natural history of breast cancer has been suggested [33]. Androgens have been used in the past to treat breast cancer, albeit with modest response rates (e.g., ~20%) that were further limited by severe adverse effects, such as masculinization [34–37]. Some preclinical evidence has demonstrated that estrogen depletion induced by AIs further sensitizes breast cancer cells to the antiproliferative effects of androgens [38, 39], potentially suggesting an additional and complementary anticancer mechanism for steroidal AIs. However, research is needed to determine whether steroidal AIs, such as exemestane, are capable of exerting any androgenic effect in breast cancer that is clinically relevant.

When considering the androgenic properties of AIs, differential effects on healthy tissue may also affect clinical benefit for breast cancer patients. Work in model systems suggests that exemestane treatment may lead to fewer adverse effects related to bone loss than nonsteroidal AIs because of its androgenicity [40–42]. Preclinical studies have demonstrated that these effects are related to activation of the AR by exemestane in osteoblasts [31, 40]. Several clinical findings support a lower degree of bone loss with exemestane [43–46]. One might expect that the steroidal structure of exemestane may lend itself to an androgenic effect on bone that would be evident by a rise in bone formation markers (such as procollagen type 1 N-propeptide) not present with the nonsteroidal AIs. However, two studies of similar design in human volunteers, comparing the effects of steroidal AIs with those of nonsteroidal AIs on markers of bone turnover, have produced conflicting results—one showing a significant rise in bone formation markers and the other not [46, 47]. Further evidence comes from the Bone Substudy of the Intergroup Exemestane Study, which demonstrated a smaller magnitude of bone mineral density loss following 1–2 years of exemestane treatment compared with historical reports of bone density loss following treatment with anastrozole or letrozole in postmenopausal women with breast cancer [43]. Long-term and head-to-head clinical trials monitoring the incidence of bone fractures are needed to determine the extent of the relative effects of exemestane compared with nonsteroidal AIs.


   CLINICAL IMPLICATIONS
Top
 Abstract
 Introduction
 Interactions with Aromatase
 Androgenic Versus Nonandrogenic...
 Clinical Implications
Summary
 Conclusions
 Author Contributions
 References
 
Crossresistance and Sequential Therapy
Observations from many clinical studies have suggested that crossresistance between steroidal and nonsteroidal AIs does not always occur (Table 2) [48–58]. These efforts have followed the seminal study by Murray and Pitt showing that breast cancer patients previously treated with the first-generation nonsteroidal AI aminoglutethimide subsequently responded to 4-hydroxyandrostenedione [50]. In general, objective response rates with a second-line AI are not high (0%–26%), but clinical benefit (which includes stable disease of ≥6 months' duration) is observed in 20%–62% of patients. This effect is observed regardless of the treatment sequence: nonsteroidal AI followed by steroidal AI [48–56] or steroidal AI followed by nonsteroidal AI [55, 57]. It must be noted that these were open-label trials, many of which were single-center studies with a small number of enrolled patients, receiving a range of prior and/or concomitant therapies (e.g., chemotherapy), and at least one study used a higher dose of the second AI than is recommended [51].


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  		Table 2. Response to third-line sequential treatment with aromatase inhibitors/inactivators in postmenopausal women with metastatic breast cancer

 
Recently, results from the phase III Evaluation of Fulvestrant versus Exemestane Clinical Trial have become available [59], in which patients with advanced hormone-responsive breast cancer refractory to a nonsteroidal AI were randomized to receive either fulvestrant or exemestane. As in earlier sequential therapy studies, patients receiving second-line exemestane treatment had a low response rate (6.7%), although the clinical benefit rate was 31%. However, the aggregate of clinical evidence indicates that patients whose disease becomes resistant to one AI may still respond to a different class of AI.

Interestingly, corresponding data on the crossresistance of AI classes in experimental systems are lacking. However, a recent study using MCF-7aro cells made resistant to AIs indicates that differential patterns of gene expression are found according to different AIs, again suggesting that mechanisms of resistance are different [60, 61].

Potential explanations for the lack of crossresistance between steroidal and nonsteroidal AIs include (a) the nature of the interaction with the enzyme's active site, (b) differential sensitivities of aromatase variants to specific compounds, (c) androgen-agonistic effects, and (d) inherent differences in potencies among AIs. The validity of these explanations, as well as any optimal treatment sequence for resistant disease (e.g., nonsteroidal followed by steroidal versus steroidal followed by nonsteroidal), remains to be determined.

Combination Therapy with Selective ER Modulators
In experimental models, combination therapy with the selective estrogen receptor modulator (SERM) tamoxifen and the nonsteroidal AI anastrozole or letrozole did not improve the antitumor efficacy of the nonsteroidal AI alone [62, 63]. These results contrast with those of the steroidal AI exemestane and tamoxifen, wherein the combination was more effective in reducing tumor growth than either agent alone in an experimental model (Figure 3) [64, 65]. A mechanism explaining the additive effects of the steroidal AI exemestane in combination with tamoxifen has not been established and warrants further evaluation.


Figure 3
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  		Figure 3. The effect of exemestane alone or in combination with tamoxifen on the growth of MCF-7Ca breast tumor xenografts in ovariectomized athymic nude mice.

Abbreviations: EXE, exemestane; TAM, tamoxifen.

Adapted with permission from Brodie A, Jelovac D, Macedo L et al. Therapeutic observations in MCF-7 aromatase xenografts. Clin Cancer Res 2005;11:884–888.

 
Clinical findings from the Arimidex, Tamoxifen, Alone or in Combination trial demonstrated that the combination of anastrozole and tamoxifen was not more efficacious than tamoxifen alone [66]. Previous studies combining aminoglutethimide and tamoxifen in patients with metastatic disease also revealed no superiority compared with either monotherapy [67]. The corresponding randomized study comparing a tamoxifen and steroidal AI combination with tamoxifen alone has not yet been performed.

Based on an initial finding that the first clinically used AI, aminoglutethimide, enhances tamoxifen clearance in humans [67], a number of studies have evaluated potential interactions between third-generation AIs and tamoxifen. Pharmacokinetic analyses have shown that coadministration of tamoxifen and nonsteroidal AIs reduces plasma levels of the AI by approximately 30%–40% compared with administration of the nonsteroidal AI alone [68, 69], although this was not considered to be the cause of the lower efficacy of the combination. In contrast, coadministration of exemestane and tamoxifen showed no evidence of pharmacokinetic interaction relative to either agent alone [70, 71]. More recently, no pharmacokinetic interaction was found by giving exemestane in combination with the SERM raloxifene [32].

Taken together, these results suggest that combination therapy with tamoxifen or another SERM and the steroidal AI exemestane should be investigated further.

Ongoing Clinical Trials
It is not currently possible to draw meaningful conclusions regarding the differential clinical effects on efficacy between steroidal and nonsteroidal AIs because of a lack of head-to-head comparisons between AIs in large randomized trials. Issues of endocrine effectiveness, safety, sequence, and combination treatment still remain. In this respect, the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) MA-27 trial is directly comparing a steroidal AI (exemestane) with a nonsteroidal AI (anastrozole) in postmenopausal women with hormone-sensitive primary breast cancer. The primary endpoint of the 5-year study is event-free survival; two bone substudies are evaluating the effects of the respective AIs on bone metabolism in women with or without osteoporosis pretreatment. In addition, two ongoing, placebo-controlled, international breast cancer prevention trials are separately evaluating exemestane (ExCel [NCIC CTG MAP3]) and the nonsteroidal AI anastrozole (International Breast Cancer Intervention Study II, IBIS-II) using similar study designs in women at increased risk for breast cancer. A crosscomparison of the efficacy and end-organ effects of these two very similarly designed trials will be informative.


   SUMMARY
Top
 Abstract
 Introduction
 Interactions with Aromatase
 Androgenic Versus Nonandrogenic...
 Clinical Implications
 Summary
Conclusions
 Author Contributions
 References
 
Although both steroidal and nonsteroidal AIs block aromatase activity, there are distinct differences between the classes. The differences relate to the type of binding to the aromatase enzyme (irreversible or reversible binding for steroidal or nonsteroidal AIs, respectively) and potential androgenic effects of exemestane, which may exert additional effects. Based on preclinical and clinical studies, there does not appear to be an advantage in combining the SERM tamoxifen with a nonsteroidal AI as initial therapy. However, preclinical findings suggest that there may be an advantage in combining tamoxifen with steroidal AIs. This type of combination should be investigated further in controlled clinical trials. Steroidal and nonsteroidal AIs are being directly compared in an ongoing head-to-head randomized controlled trial. Consequently, future results will help determine whether the different classes of AI have distinct efficacy or safety effects in the treatment or prevention of breast cancer.


   CONCLUSIONS
Top
 Abstract
 Introduction
 Interactions with Aromatase
 Androgenic Versus Nonandrogenic...
 Clinical Implications
 Summary
 Conclusions
Author Contributions
 References
 
The answer to the question "are there differences between steroidal and nonsteroidal AIs?" is undoubtedly "yes," but more evidence is needed to determine the mechanism and clinical implications. Preclinical studies are needed to determine whether differences in the interaction with aromatase, the existence of mutant tumor aromatase, variations in molecular pathways leading to resistance, and androgenic effects might mean that particular tumors and circumstances are more optimally treated by one class of AI than another. At present, the differential properties of the AI classes are not used to plan patient management, which is still largely based on results from clinical trials of individual AIs against tamoxifen or physician preferences and experience. Thus, there are still many unanswered questions that can only be addressed by head-to-head clinical trials of the AI classes.


   AUTHOR CONTRIBUTIONS
Top
 Abstract
 Introduction
 Interactions with Aromatase
 Androgenic Versus Nonandrogenic...
 Clinical Implications
 Summary
 Conclusions
 Author Contributions
References
 
Conception/design: William R. Miller, John Bartlett, Enrico di Salle, Paul E. Goss

Provision of study materials or patients: Angela M. H. Brodie, Antonio Llombart, Hironobu Sasano, Paul E. Goss

Collection/assembly of data: Paul E. Goss

Data analysis and interpretation: William R. Miller, John Bartlett, Robert W. Brueggemeier, Enrico di Salle, Hironobu Sasano, Paul E. Goss

Manuscript writing: William R. Miller, John Bartlett, Angela M. H. Brodie, Robert W. Brueggemeier, Enrico di Salle, Per Eystein Lønning, Nicolai Maass, Thierry Maudelonde, Paul E. Goss

Final approval of manuscript: William R. Miller, John Bartlett, Angela M. H. Brodie, Robert W. Brueggemeier, Enrico di Salle, Per Eystein Lønning, Antonio Llombart, Nicolai Maass, Thierry Maudelonde, Hironobu Sasano, Paul E. Goss

The authors were responsible for the substance of the paper. Concept and content were provided by the authors as a group. Editorial support was provided by Vicki M. Houle, Ph.D., and Chris A. Kirk, Ph.D., of Complete Healthcare Communications, Inc., and was funded by Pfizer Inc. They provided assistance in researching and ordering reference articles and rationalizing authors' input into an initial manuscript draft, including development of the EndNote library and copyediting. They also provided administrative assistance in terms of collating and incorporating edits from all authors, coordinating review by all authors, and ensuring their participation according to ICMJE guidelines, and formatting the manuscript and preparing the submission packet per The Oncologist guidelines.


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Top
 Abstract
 Introduction
 Interactions with Aromatase
 Androgenic Versus Nonandrogenic...
 Clinical Implications
 Summary
 Conclusions
 Author Contributions
 References
 

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P. Hadji, M. Ziller, D. G. Kieback, W. Dornoff, H. W. Tessen, T. Menschik, J. Kuck, F. Melchert, and A. Hasenburg
Effects of exemestane and tamoxifen on bone health within the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial: results of a German, 12-month, prospective, randomised substudy
Ann. Onc., July 1, 2009; 20(7): 1203 - 1209.
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