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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 56Clinical Use of Aromatase Inhibitors in Breast Carcinoma

, MD.

Antiestrogens are the mainstay of palliative endocrine therapy in women with metastatic hormone-dependent breast cancer. Patients who respond but whose disease later progresses on this form of therapy frequently respond to second-line endocrine treatment. It has, therefore, become important to develop effective second-line therapies that interfere with hormonal action through mechanisms other than blockade of the estrogen receptor. A new class of compounds, the aromatase inhibitors, provide just such an approach to the endocrine treatment of breast cancer. Increasing use of these agents has essentially eliminated the need for major endocrine ablative procedures, such as adrenalectomy or hypophysectomy, as palliative therapy for metastatic breast cancer.

In postmenopausal or castrated women, the major source of estrogen derives not from the ovaries but from the conversion of the adrenal hormones androstenedione and, to a lesser extent, testosterone to estrone. This enzymatic conversion occurs at extra-adrenal or peripheral sites such as fat, liver, and muscle and is catalyzed by the aromatase enzyme complex. Some breast cancer tissues also contain aromatase.

Potent aromatase inhibitors which further lower the levels of both circulating and intratumoral estrogens are now recognized as useful agents in the treatment of postmenopausal women with hormone-sensitive breast cancer. In this chapter, we will discuss recent advances in our knowledge of the molecular biology, cellular expression, and physiologic importance of the enzyme aromatase. We will also discuss the preclinical studies and results of clinical trials that support the use of aromatase inhibitors as an approach to the treatment of hormone dependent breast cancer.

Biology of Aromatase

Gene Structure and Regulation

Aromatase consists of a complex containing a cytochrome P450 heme–containing protein as well as the flavoprotein NADPH cytochrome P450 reductase.1 The gene coding for the cytochrome P450 protein (P450AROM) exceeds 70 kilobases (kb) and is the largest of the cytochrome P450 family of steroidogenic genes, comprising 10 exons and intervening introns of varying lengths.2 The cDNA of the aromatase gene contains 3.4 kb and encodes a polypeptide of 503 amino acids with a molecular weight of 55 kd. Approximately 30% homology exists with other cytochrome P450 proteins. Because its overall homology to other members of the P450 superfamily is low, aromatase belongs to a separate gene family designated CYP19. Aromatase expression occurs in many organs, including the ovary, placenta, hypothalamus, liver, muscle, adipose tissue, and the cancerous breast tissue itself.1,3 Aromatase expression is controlled by multiple agents, which include cytokines, cyclic AMP, gonadotropins, phorbolesters, glucocorticoids, and growth factors.4 Such regulation is associated with comparable changes in the levels of P450 AROM mRNA.1,5 By contrast, the NADPH cytochrome P450 reductase component is much less markedly affected. At least four major promoter sites have been identified, which account for the tissue-specific regulation of the human P450 AROM gene.4 Of particular relevance to breast cancer, a unique promoter, 1.4, has been identified in breast adipose tissue.6 This observation raises the possibility that by blocking promoter 1.4-directed gene transcription, it may be possible to achieve tissue-selective estrogen withdrawal without subjecting the patient to whole-body chemical castration.

Aromatase catalyzes three separate steroid hydroxylations involved in the conversion of androstenedione to estrone. The first two give rise to 19-hydroxy and 19-aldehyde structures, and the third, although still controversial, probably also involves the C-19 methyl group with release of formic acid.7

Sites of Estrogen Biosynthesis


In premenopausal women, the ovary is the most important site of aromatase and estrogen production. Luteinizing hormone (LH) controls the production of androstenedione by the theca cell compartment, while follicle-stimulating hormone (FSH) upregulates aromatase expression in granulosa cells. Acting in concert, LH stimulates production of the substrate for aromatase, whereas FSH increases the amount of the enzyme so that estradiol production can increase by eight- to 10-fold at the time of ovulation. Attempts to interrupt ovarian estrogen biosynthesis with first-generation aromatase inhibitors have failed because of the reflex increases in FSH and LH secretion, which counteract the inhibitory action of the drug8 (Fig. 56.1). It is conceivable that with the introduction of more potent aromatase inhibitors, it may be possible to block ovarian steroidogenesis.

Figure 56.1. A.

Figure 56.1

A. Diagrammatic representation of the hypothalamic-pituitary-ovarian axis. The triangle represents the hypothalamus; the ovoid, the pituitary; and the circle, the ovary. (Key: GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone; FSH = follicle (more...)

Extraglandular Aromatase

In postmenopausal women, estrogen synthesis takes place nearly exclusively in extraglandular tissues. Androstenedione, produced primarily by the adrenal and, to a negligible extent, by the ovary is converted to estrone by aromatase in the periphery, such as in adipose tissue.9 The enzyme 17-hydroxysteroid dehydrogenase then converts estrone to estradiol. Estrone can also be conjugated into estrone sulfate to form a slowly turning over storage pool, with a potential for back-conversion to estrone. Through the androstenedione-to-estrone pathway, postmenopausal women produce approximately 100 mg of estrone per day and more, if they are obese.10 A substantial fraction of estrone is converted to estradiol to produce circulating concentrations of 10 to 20 pg/mL (Fig. 56.2).

Figure 56.2. Sources of estrogen in postmenopausal women.

Figure 56.2

Sources of estrogen in postmenopausal women. Adrenal gland secretes androstenedione (A), which enters plasma and then tissue. Extraglandular tissues contain the enzymes necessary to convert A to estrone (E1), and to estradiol (E2) or to estrone sulfate (more...)

Local Estrogen Synthesis in Breast Tumors

The levels of estradiol in human breast tumor tissues are an order of magnitude higher (4- to 6-fold) than those in plasma.11,12 The mechanisms responsible for maintenance of high tissue estradiol concentrations are not completely defined but are likely to involve local production of estradiol by the tumor itself.13 Several investigators have identified aromatase activity in human breast tumors.14,15 Approximately two-thirds of human breast cancers contain appreciable levels of aromatase activity. As we will discuss below, however, aromatase expression is heterogeneous such that high activity is present in focal clusters of specific cell types. An additional pathway of local estrogen production by the tumor could involve the enzyme sulfatase, which catalyzes the conversion of estrone sulfate to estrone. Levels of this enzyme are actually higher in human breast tumors than those of aromatase; however, the affinity of sulfatase for the substrate is much lower than that of aromatase.13 Therefore, the relative importance of sulfatase versus aromatase for estradiol biosynthesis in situ in human breast cancer tissue remains to be defined (Fig. 56.3).

Figure 56.3. Diagrammatic representation of the biosynthetic pathways for estrogen production locally in breast tumors.

Figure 56.3

Diagrammatic representation of the biosynthetic pathways for estrogen production locally in breast tumors. The shaded area indicates breast tumor tissue.

Heterogeneous Cellular Expression of Aromatase by Normal and Malignant Breast Tissue

Using competitive RT-PCR, Bulun and Simpson quantified P450 AROM transcripts in breast adipose tissue from mastectomy specimens. They observed that the highest transcript levels were localized to tumor-bearing quadrants. In addition, using quantitative morphometry, they found the highest proportions in adipose stromal cells in these quadrants.4 Their data suggest that regional differences in relative proportions of histologic components of the breast tissue (i.e., adipocytes versus stromal cells) are the primary cause of estrogenic concentration gradients, since regions containing a higher number of stromal cells are the sites of elevated P450 AROM transcript levels. The authors postulate that once neoplastic transformation has occurred, tumor growth is promoted by locally increased estrogen levels. Secretory products of the tumor stimulated by estrogens may, in turn, further increase aromatase gene expression in the surrounding adipose tissue. Thus, a positive feedback loop may be created, whereby locally produced estrogens and tumor-derived factors act in a paracrine-autocrine fashion to sustain growth and development of the tumor. A similar physiologic construct is also suggested by Santen and co-workers, who analyzed aromatase expression by human breast tumors using immunohistochemistry. They observed that the highest degree of aromatase expression occurred in stromal spindle cells, whereas tumor epithelial, stromal, inflammatory, and normal breast elements contained lesser amounts (Fig. 56.4). Furthermore, a statistically significant correlation was found between biochemical measurements of aromatase and the stromal spindle cell histologic score.16 Heterogeneity in aromatase expression by human breast cancers has also been reported by other investigators, at both the message and the protein levels.17,18 In the aggregate, these observations provide further support for the possibility that human breast tumors contain biologically relevant amounts of aromatase, exerting autocrine or paracrine effects.

Figure 56.4. Aromatase immunohistochemistry color photomicrographs.

Figure 56.4

Aromatase immunohistochemistry color photomicrographs. (Modified from Santen et al. with permission.) A. A section of human breast tumor stained with antiaromatase antibody. Several isolated tumor epithelial cells are present with densely stained cytoplasm (more...)

Historical Development of Aromatase Inhibitors

Inasmuch as aminoglutethimide is the prototype of later aromatase inhibitors, it is useful first to review the information gleaned from the early experimental and clinical experience with this agent.

Aminoglutethimide, a derivative of the sedative agent glutethimide, was initially introduced into clinical medicine as an anticonvulsant and was later recognized to be an inhibitor of cytochrome P450 N–mediated steroid hydroxylations, particularly those involving the cholesterol side-chain cleavage enzyme.19 The first clinical use of aminoglutethimide as therapy for breast cancer attempted to produce a “medical adrenalectomy” by blocking cholesterol side-chain cleavage.20 Replacement glucocorticoid was added to compensate for the inhibition of cortisol biosynthesis. Only later was it recognized that the estrogen-lowering effect induced by the aminoglutethimide and glucocorticoid regimen was due primarily to inhibition of the aromatase enzyme.21,22 This conclusion was inferred from the unexpected observation that androstenedione levels were unchanged, since blockade of cholesterol side-chain cleavage activity should have resulted in suppressed adrenal androgen secretion.23 Indeed, direct isotopic kinetic studies in patients confirmed the activity of aminoglutethimide as an aromatase inhibitor in vivo.24 The effects of this compound, however, are rather nonspecific, since the drug affects a number of hydroxylation steps in the metabolic conversion of cholesterol to active steroid products.

Clinical Efficacy

An overall compilation of clinical responses to aminoglutethimide plus glucocorticoid in women with breast cancer reveals results similar to those expected from other forms of endocrine therapy, that is, approximately a third of all patients experience either complete or partial tumor regression, while for patients with estrogen receptor–positive tumors, the response rate is 54%. The mean duration of response is 13 months and mean survival 20 months. Soft tissues respond most frequently, followed by lymph nodes, bone, lung/pleura, viscera, and liver.20

Randomized comparative trials of aminoglutethimide plus hydrocortisone versus other endocrine therapies provide a more precise assessment of efficacy. The aminoglutethimide regimen was equally effective when compared with surgical adrenalectomy25 or trans-sphenoidal hypophysectomy in small controlled trials.26 Similarly, when compared with tamoxifen, aminoglutethimide plus hydrocortisone produces responses as frequently and for a comparable duration.27 A trend toward greater healing of osteolytic lesions was observed with aminoglutethimide plus hydrocortisone than with tamoxifen.

Although the efficacy of aminoglutethimide plus hydrocortisone was similar to that of other agents, cross-resistance between aminoglutethimide plus hydrocortisone and tamoxifen or progesterone therapy was not complete. Overall, 31% of patients treated initially with tamoxifen later respond objectively to aminoglutethimide plus hydrocortisone. Patients can be subdivided into those that initially respond to tamoxifen and later relapse, and those whose disease initially progresses. Fifty percent of patients who initially respond objectively to tamoxifen and later relapse experience an objective response to aminoglutethimide plus hydrocortisone. On the other hand, only 25% of tamoxifen nonresponders were objectively benefited by aminoglutethimide plus hydrocortisone. Although somewhat controversial, some studies suggest that responders to progestin therapy also may benefit from aminoglutethimide plus hydrocortisone on relapse.27

Side Effects

Patients receiving the standard dose of aminoglutethimide 1,000 mg/d experienced a wide range of side effects during the induction of therapy. The major problems include drug rash, fever, and lethargy. Skin rash is a particularly important side effect but it resolves spontaneously, even without discontinuation of therapy in the majority of patients. Approximately a third of women require mineralocorticoid replacement with 9α-fluorohydrocortisone (Florinef) because of the inhibition of aldosterone production.28 Another 5% of patients require thyroxine supplementation because of the inhibitory effects of aminoglutethimide on thyroid hormone synthesis, a cytochrome P450 N–dependent process.29 In the remainder, thyroid-stimulating hormone (TSH) levels increase sufficiently to completely overcome the blockade of thyroxine biosynthesis.

The various side effects preclude continuing treatment in 8 to 15% of patients, particularly elderly women; however, many of these symptoms resolve completely or diminish in severity with treatment for longer than 6 weeks. One possible basis for the reduction in side effects over time is the fact that aminoglutethimide accelerates its own metabolism from 12 hours to approximately 7 hours, presumably through hepatic enzyme induction.30

The frequency and severity of side effects from aminoglutethimide, particularly when compared with tamoxifen, has led to attempts either to reduce the dose of aminoglutethimide31 or else to develop less toxic compounds.

Development of Improved Aromatase Inhibitors

The successful use of aminoglutethimide provided an impetus to investigate further the concept of inhibiting estrogen biosynthesis as a means of treating breast cancer. The problem of the multiple actions of aminoglutethimide, its associated side effects, and the need for exogenous glucocorticoid spurred interest in the development of second- and third-generation aromatase inhibitors. Progressively, these newer compounds are demonstrating increasing potency, greater specificity, and reduced toxicity, compared with aminoglutethimide. For example, compounds such as 4-hydroxyandrostenedione, originally studied by Brodie and colleagues, were designed as selective inhibitors of aromatase.32 Several new compounds have been studied, and the most clinically important ones will be reviewed in this chapter.


A convenient classification divides the aromatase inhibitors into the mechanism-based, or suicide, inhibitors (type 1) and those that are competitive inhibitors (type II). Suicide inhibitors initially compete with the natural substrate (i.e., androstenedione and testosterone) for binding to the active site of the enzyme. The enzyme, then, specifically acts on the inhibitor to yield reactive alkylating species, which form covalent bonds at or near the active site of the enzyme. Through this mechanism, the enzyme is irreversibly inactivated. Competitive inhibitors, on the other hand, bind reversibly to the active site of the enzyme and prevent product formation only as long as the inhibitor occupies the catalytic site. The available mechanism-based inhibitors are exclusively steroidal in structure, whereas the competitive inhibitors are nonsteroidal compounds (Table 56.1).

Table 56.1. Classification of Aromatase Inhibitors.

Table 56.1

Classification of Aromatase Inhibitors.

In seeking effective aromatase inhibitors, two considerations are paramount: intrinsic biologic activity and specificity of inhibition. In theory, mechanism-based or suicide inhibitors (type I) should be preferable to competitive inhibitors because of their irreversible action on the enzyme. Clinically, their duration of action in vivo should be prolonged, related primarily to the rate at which new enzyme can be synthesized.

Generally speaking, nonsteroidal inhibitors are more likely than steroidal compounds to lack specificity, since they have a potential for blocking several cytochrome P450-mediated steroid hydroxylations. On the other hand, steroidal inhibitors or their metabolites have greater potential for producing estrogen, androgen, glucocorticoid or progestin agonist or antagonistic effects through the inherent properties of their structures. It is unclear whether these theoretical considerations will prove to be of any practical or clinical significance. Structures of the currently available aromatase inhibitors are shown in Figure 56.5.

Figure 56.5. Structure and classification of representative aromatase inhibitors.

Figure 56.5

Structure and classification of representative aromatase inhibitors. Compounds are shown in approximate order of increasing specificity and potency of aromatase inhibition.

Mechanism-Based (Suicide) Inhibitors


Lentaron (Formestane; 4-OHA; 4-hydroxyandrost-4-ene-3,17-dione) is a structural analogue of androstenedione. It was the first steroidal suicide-type aromatase inhibitor to enter clinical trials. Using the placental aromatase assay system in vitro, 4-OHA was shown to be 60-fold more potent than aminoglutethimide (Ki=4.1δM). Extensive studies revealed no estrogenic, antiestrogenic, or antiandrogenic properties;33 however, transformation to 4-hydroxytestosterone occurs, and androgenic effects can be demonstrated under certain circumstances.34

4-hydroxyandrostenedione (Lentaron, Formestane) has been studied extensively in postmenopausal women with breast cancer. In a phase I study, postmenopausal women received 500 to 1,000 mg of 4-OHA by weekly intramuscular injection.35 Although the drug has a short plasma half-life, concentrations of drug during chronic therapy and 1 week after the last injection ranged from 0.7 to 23.2 ng/mL (mean 7.8 ng/mL). This might reflect a depot effect of the injected drug. During therapy, plasma estradiol levels fell from 7.2 ± 0.8 (SEM) pg/mL to 2.6 ± 2.8 pg/mL from 1 to 41 months after initiating treatment.

Data from four phase II clinical trials of 4-OHA demonstrated a 33% objective regression rate of breast cancer in postmenopausal patients previously treated with multiple endocrine therapies. Toxicity included 6 patients with sterile abscesses due to intramuscular injections, 2 of sufficient severity to warrant discontinuation of therapy. No androgenic effects were observed.36

Höffken and colleagues conducted a large trial of 4-OHA in postmenopausal women.37 Patients initially received 500 mg intramuscularly every 2 weeks for 6 weeks and then 250 mg every 2 weeks thereafter. Plasma estradiol levels fell from baseline values of 10 to 11 pg/mL to levels of approximately 4 pg/mL for up to 7 months of therapy. The drug appeared specific, since no reduction of cortisol or symptoms of cortisol deficiency were observed. Of 86 evaluable patients, there were 2 complete and 19 partial remissions (24%), and 26 experienced disease stabilization (30%). Side effects included minor systemic symptoms in 11% (hot flashes, constipation, alopecia, pruritus) and local symptoms in 8% (pruritus, local pain, erythema). These side effects resulted in discontinuation of therapy in only 2% of patients. Phase III trials are now ongoing to compare this inhibitor with standard endocrine therapies. In general, 4-OHA is better tolerated than aminoglutethimide.

4-hydroxyandrostenedione has also been given orally. Even though there is a marked first-pass effect with conversion in the liver to a glucuronidated derivative, oral doses of 250 mg reduce plasma estradiol by 53% and doses up to 1,000 mg produce no further suppression. The response rate after 3 months of therapy was 33%, and the only serious side effect from the oral dosage was leukopenia in a single patient.38


Exemestane (6-methylene-androsta-1,4-diene-3,17-dione) is an irreversible (type I or mechanism-based) aromatase inhibitor.39–41 Its Ki for competitive inhibition is 10.2 nmol/L and for irreversible inactivation is 26 nmol/L. Single-dose administration reveals a major reduction of plasma estrogens with this compound.41 A dose of 25 mg/d inhibited aromatase activity as documented by the isotope kinetic technique by 97.9%. Phase II clinical trials of exemestane in postmenopausal patients with metastatic breast cancer showed very promising results with response rates ranging from 11 to 28%, depending on the extent of prior endocrine therapy.42,43 In a large randomized phase III trial conducted in postmenopausal patients with metastatic breast cancer no longer responding to tamoxifen, exemestane 25 mg PO daily was compared to megestrol acetate 40 mg qid. This multi-center international trial enrolled a total of 769 patients. Patient and disease characteristics were equally distributed between the two arms of the trial. Kaufman and colleagues reported a 15% objective response rate among the 366 women receiving exemestane, and this was similar to the 12.4% response rate for the women treated with megestrol acetate. An additional 22% of women in each treatment group experienced stabilization of their disease. Exemestane produced a statistically significant increase in the median duration of overall clinical benefit (60.1 versus 49 weeks, p = .025) as well as in the median time to tumor progression. Furthermore, in this trial, the authors reported that the median survival was also significantly longer in patients receiving exemestane. These results are summarized in Table 56.1. Side effects associated with exemestane treatment were mild and included hot flashes, nausea, and fatigue in a relatively few patients. Undesirable weight gain was also less frequent among women receiving exemestane, compared with that observed in women treated with megestrol acetate.44

Competitive Inhibitors

Second-Generation Nonsteroidal Competitive Inhibitors

Several nonsteroidal competitive inhibitors of aromatase are now clinically available. The imidazole compounds have potent effects on a number of cytochrome P450-mediated steroid hydroxylation steps. Ketoconazole, for example, blocks C1720 hydroxylase at low concentrations and aromatase at high concentrations.45 This observation suggested that theoretically, compounds could be found which would exert relatively specific effects on certain P450-mediated steroid hydroxylations with little activity on others. In fact, the several new compounds discussed below are indeed potent competitive inhibitors of aromatase but lack significant cholesterol side-chain cleavage activity. Specificity is not absolute, since high concentrations of drug may block other P450-mediated steps as well.


Fadrozole (CGS 16949A; 4-(5,6,7,8-tetrahydroimidazo[1,5a]-pyridin-5yl) benzonitrile monohydrochloride) is a highly potent inhibitor of aromatase with a Ki of 0.19 nM (versus 600 nM for aminoglutethimide).46,47 Cholesterol side-chain cleavage activity is minimal but C11-hydroxylase inhibitory effects are observed in vitro at high drug concentrations (i.e., 1026 M). Negligible toxicity was observed in animal studies.48

Initial dose-seeking studies conducted in patients demonstrated effective aromatase inhibition at doses of 1.8 to 4.0 mg daily.49 A phase II study then compared doses of 0.6 mg three times daily, 1 mg twice daily, and 2 mg twice daily. Maximal suppression of plasma and urinary estrogens occurred at a dose of 1.0 mg twice daily, and minimal effects on cortisol secretion were observed. Basal cortisol and adrenocorticotropin (ACTH) levels were unaffected, and cortisol levels increased to more than 20 mg/dL after exogenous synthetic C124 ACTH (Cortrosyn) administration in all patients. Basal levels of aldosterone also remained stable following administration of all three drug doses. There were no changes in urinary or plasma sodium or potassium, nor in standing blood pressure to suggest a clinical state of aldosterone deficiency; however, Cortrosyn-stimulated aldosterone levels were significantly blunted at all three doses.50

Clinical data from several phase II trials of fadrozole demonstrated an overall objective response rate in postmenopausal patients with advanced breast cancer that ranged from 3 to 23%. In one trial, objective regressions were recorded in 11 of 54 patients (20%).51 Twenty-eight percent of 18 patients treated by Possinger and colleagues experienced an objective response.52 Falkson’s group reported a response rate of 23% (10% complete responses, 13% partial responses) among 78 patients.53 All studies report a higher rate of disease stabilization, and the median time to treatment failure ranges from 4 to 16 months. It should be noted that most patients enrolled in these early trials had received several prior endocrine and other therapies. Toxicity attributed to this agent is mild and consists mainly of nausea, anorexia, fatigue, and hot flashes.

Two large multi-center phase III trials in the United States comparing fadrozole hydrochloride with megestrol acetate in patients who had received only tamoxifen as prior hormone therapy have been completed. These studies accrued a total of 672 patients. Final clinical results as reported by Buzdar and colleagues showed that there were no significant differences between the two treatment arms of the trials with respect to time to progression, objective response rates, response duration, or overall survival. In these two trials, responses to megestrol acetate were somewhat lower than expected from previous studies with objective response rates of 11 and 13%, respectively. Randomized patients receiving fadrozole experienced objective responses of 11 and 16% which did not differ significantly from those with megestrol. Stable disease for more than 6 months occurred in 25% of patients receiving fadrozole and 20% taking megestrol acetate. Nausea was more frequent for fadrozole than megestrol acetate in both trials (22 versus 13% and 36% versus 11%, respectively). In contrast, edema was more common with megestrol acetate (21% versus 12% and 19% versus 12%) as was weight gain.54

The potency of fadrozole, its relatively specific effects on aromatase, and its lack of toxicity indicate that this second-generation aromatase inhibitor represents a major improvement over aminoglutethimide for treatment of patients with breast cancer. The drug is approved in Japan for this particular clinical indication.

Third-Generation Nonsteroidal Competitive Inhibitors

Third-generation aromatase inhibitors are the most potent and highly selective members of this class of drugs. Three agents have undergone extensive clinical study and are discussed below.


Anastrozole (arimidex: ICI-D1033; 2,2’{5-(1H-1,2,4-triazol-1-ylmethyl)-1.3-phenylene} bis(2-methyl-propio-nonitrile) is a potent and selective benzyltriazole derivative. At a concentration of 15 nmol/L this compound inhibits aromatase activity by 50%. In rodents, maximal hormonal suppression is achieved with an oral dose of 0.1 mg/kg. Activity is assessed by examining the degree of inhibition of ovulation and of androstenedione-induced uterine hypertrophy. Studies conducted in monkeys demonstrate similar inhibitory potency when expressed on an mg/m2 basis and assessed by measurement of plasma estradiol. Studies in women demonstrated suppression of plasma estrogen to levels approaching the limits of assay sensitivity. Anastrozole produced no effects on aldosterone, cortisol, or thyroxine synthesis. The estimated elimination half-life in humans is 32.2 hours.55

Anastrozole was the first aromatase inhibitor to be approved in the United States for the management of advanced breast carcinoma in postmenopausal women. This approval was based on results of two pivotal trials that together accrued a total of 764 patients randomized to receive either anastrozole (1 mg PO /d ) or anastrozole (10 mg PO /d) or megestrol acetate 40 mg qid.56 These patients had metastatic disease that was progressing, following therapy with tamoxifen given either in the adjuvant setting or as first-line endocrine therapy for metastatic disease. Patients in the three arms of the trial had similar prognostic characteristics including age, estrogen receptor status, disease-free interval, and sites of metastases. Results from these important trials showed similar overall response rates in either dose of anastrozole or to megestrol acetate. No statistically significant dose-response differences were observed between the 1- and the 10-mg daily dosage. The rates of overall objective response of 10.3% and 8.9%, respectively, were somewhat low. Overall responses including complete and partial objective response rates and stabilization of disease of > 6 months (i.e., total clinical benefit) averaged 35%. It should be noted that recent studies have demonstrated that disease stabilization for > 6 months is a meaningful clinical parameter since patients experiencing this response survive equally as long as patients undergoing partial objective response.57 Patients with complete or partial objective responses or stable disease survive longer than those with disease progression.

In initial reports, the third-generation aromatase inhibitor, anastrozole, was considered superior to megestrol acetate because it was better tolerated. It was associated with less undesirable weight gain, dyspnea, fever, and thromboembolic events, compared with megestrol acetate.56 Since there were no differences between the two doses of anastrozole, the drug was approved at a dose of 1 mg daily.

Surprisingly, with further maturity, combined data from the two pivotal trials show that anastrozole conferred a survival advantage, compared with the progestin (median of 26.7 months versus 22.5 months) (Table 56.2). The 2-year survival was 56.1% for the group of patients receiving anastrozole (1 mg), compared with 46.3% for patients treated with megestrol acetate.59 The demonstration that anastrozole has superior efficacy with respect to overall survival and reduced side-effects when compared with megestrol acetate would suggest that the aromatase inhibitor should be used as second-line therapy in preference to megestrol acetate.58

Table 56.2. Combined Data from Phase III Trials Comparing Anastrozole, Letrozole and Exemestane to Megestrol Acetate in Postmenopausal Women Previously Treated with Tamoxifen.

Table 56.2

Combined Data from Phase III Trials Comparing Anastrozole, Letrozole and Exemestane to Megestrol Acetate in Postmenopausal Women Previously Treated with Tamoxifen.


The second aromatase inhibitor to gain approval in the United States with the indication for management of postmenopausal women with metastatic breast cancer was letrozole (Femara) Letrozole (4,4’-(1H-1,2,4-triazol-1-yl-methylene)-bis-benzonitrile) is also a potent nonsteroidal competitive aromatase inhibitor. This agent possesses considerable selectivity for aromatase. At doses >1,000 times higher than the concentration required to cause a 50% inhibition of the aromatase enzyme, letrozole does not significantly suppress either aldosterone or corticosterone in rats. Letrozole is a highly potent and selective aromatase inhibitor. When administered orally to adult female rats at a dose of 1 mg/kg/d for 14 days, letrozole decreases uterine weight to that observed after a surgical ovariectomy.60 Letrozole also causes significant regression of dimethylbenzanthracene (DMBA)-induced rat mammary tumors.

Clinical studies in normal healthy volunteers as well as dose-seeking phase I trials in postmenopausal women with advanced breast cancer showed that letrozole in a dose as little as 0.25 mg PO daily caused maximal suppression of plasma and urinary estrogens. A highly sensitive recombinant DNA-based estradiol bioassay was used to assess estradiol levels in one of these studies. The levels of estradiol were decreased by 95% to levels of 0.05 to 0.07 pmol/L as detected by this assay. This observation underscores the limitation of standard RIAs for detection of estradiol levels in patients given highly potent aromatase inhibitors.61

Additional studies established the fact that letrozole was quite selective for the inhibition of aromatase, since over a wide dose range, there were no significant changes in the levels of gonadotropins, ACTH, cortisol, aldosterone, or TSH.62,63 Early trials of letrozole in heavily pretreated postmenopausal women with metastatic breast cancer demonstrated both clinical efficacy and lack of significant toxicity.64

Approval of this agent was based on the results of two large, multi-center, randomized trials similar to design to the studies involving anastrozole. In a pivotal trial, 555 postmenopausal women with metastatic breast carcinoma progressing after treatment with tamoxifen were randomized to receive letrozole 0.5 mg daily or 2.5 mg daily) or standard doses of megestrol acetate. The women in the three treatment groups were comparable in all respects. The two doses of letrozole caused similar prompt and profound suppression of plasma and urinary estrogens. Letrozole (2.5 mg) yielded an overall response rate (complete and partial tumor regression and disease stabilization for > 6 months) of 36% and 35%, respectively, compared with 27% and 33%, respectively, for letrozole (0.5 mg) and 32% for megestrol acetate. However, the median duration of response for letrozole (2.5 mg) was 33 months, compared with 18 months for both megestrol acetate and the lower dose of letrozole. Similarly, there was a trend in time to tumor progression and survival that favors the 2.5 mg letrozole dose.65 (Figs. 56.6Figs. 56.7Figs. 56.856.9).

Figure 56.6. Phase III trial of letrozole versus megestrol acetate: objective tumor response.

Figure 56.6

Phase III trial of letrozole versus megestrol acetate: objective tumor response.

Figure 56.7. Phase III trial of letrozole versus megestrol acetate: time to failure.

Figure 56.7

Phase III trial of letrozole versus megestrol acetate: time to failure.

Figure 56.8. Phase III trial of letrozole versus megestrol acetate: duration of clinical benefit.

Figure 56.8

Phase III trial of letrozole versus megestrol acetate: duration of clinical benefit.

Figure 56.9

Figure 56.9

Phase III trial of letrozole versus megestrol acetate: survival

In a second and similar study involving 555 postmenopausal patients with advanced breast cancer progressing after tamoxifen therapy, letrozole was compared with aminoglutethimide (250 mg bid) and hydrocortisone. Letrozole 2.5-mg daily produced an objective response rate of 17% versus 12% for aminoglutethimide66 (Fig. 56.10). The median response duration was 23 months for letrozole, compared with 15 months for aminoglutethimide, and there was a statistically significant improvement in overall survival for the patients receiving letrozole. Moreover, letrozole produced less somnolence and skin rash. The results of these large, well-done, randomized trials suggest that the side-effect profile and the dosing schedules of both anastrozole and letrozole are superior to megestrol acetate and aminoglutethimide.

Figure 56.10. Phase III trial of letrozole versus aminoglutethimide: objective response.

Figure 56.10

Phase III trial of letrozole versus aminoglutethimide: objective response.


Vorozole (R83842; R76713; vorozole(s)-(6-[4-chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1H-benzotriazole) represents another highly potent and specific aromatase inhibitor with little toxicity in animal studies.67 The Ki for placental aromatase is 0.8 nM, and this agent is approximately 500-fold more potent than aminoglutethimide. From animal data, vorozole appears to be highly specific for aromatase without having major effects on other cytochrome P450-mediated steroid hydroxylations. Phase I clinical studies revealed an acute reduction of plasma estradiol to undetectable levels in normal men receiving one 10-mg dose and a 64% reduction in premenopausal women.68 Goss and co-workers reported a phase II study of vorozole in an oral dose of 2.5 mg daily given to postmenopausal women with metastatic breast cancer. Treatment-related side effects were mild and included malaise, anorexia and nausea, hot flashes, fluid retention, vaginal infection, alopecia, lightheadedness, and one allergic reaction causing lip swelling. There was profound suppression of serum estradiol and estrone from pretreatment levels. Of 27 evaluable patients, 3 (11%) had partial remission of their disease for 14, 15, and 16 months, respectively, and 14 achieved disease stabilization for a median duration of 12 months.69 In a phase III randomized clinical trial comparing vorozole to megestrol acetate in 450 postmenopausal patients with metastatic breast cancer progressing on tamoxifen, the aromatase inhibitor was superior. The response rate to vorozole was 20%, compared with 15% from megestrol, and there was a longer time to tumor progression (18 months versus 12 months). Patients receiving vorozole had fewer side effects.70 Despite these promising clinical results, vorozole has recently been withdrawn from marketing and further clinical development.

Selection of Patients for Aromatase Inhibition Therapy

Postmenopausal Women

Endocrine therapy is usually offered to patients with metastatic disease who have estrogen or progesterone receptor–positive or receptor-unknown disease. In addition to the level of receptors, clinical features that might suggest a favorable response include a long disease-free interval after initial surgery or the presence of nodal, soft tissue, bone, pleural, or nodular lung metastases. Patients with CNS involvement, extensive liver disease, lymphangitic spread of tumor in the lungs, or rapidly progressing and life-threatening disease are not ordinarily considered candidates for hormone therapy. Considerable clinical experience and data from the literature suggest that most endocrine therapies, with the possible exceptions of androgens and glucocorticoids, are equally efficacious. The decision to choose one endocrine therapy over another depends on the menopausal status of the patient, considerations of efficacy, ease of administration, cost, and side effects. Historically, of all the endocrine therapies, tamoxifen was associated with the fewest side effects. This aspect still favors tamoxifen as the endocrine therapy of first choice. Aromatase inhibitors are then considered, as either second- or third-line endocrine approaches. More recently, however, the widespread use of tamoxifen as adjuvant therapy, frequently administered for long periods, presents the clinician with a new therapeutic dilemma. A practical approach is to rely on tamoxifen as first-line therapy for patients with metastatic disease who have not received this agent in the adjuvant setting or have discontinued tamoxifen for more than a year. For other patients who are still candidates for hormone therapy, the major choices at present are between progestins, such as megestrol acetate or medroxyprogesterone acetate, and aromatase inhibitors. Several of the new-generation aromatase inhibitors are now widely available to clinicians. Given their potency, specific mode of action, and highly favorable therapeutic profile, many clinicians would now favor choosing aromatase inhibitors over progestins as second-line endocrine therapy for metastatic breast cancer71. It has been speculated that the determination of the aromatase content of a particular tumor, by either biochemical measurement or immunohistochemistry, might aid in selecting patients who are likely to respond to therapy with aromatase inhibitors. However, this concept needs further clinical testing.72,73

Premenopausal Patients

Considerations of efficacy, cost, toxicity, and ease of administration also dictate the choice of endocrine therapy in premenopausal patients. On the basis of these considerations, first-line therapy would include either tamoxifen or oophorectomy. Effective castration can be accomplished either by surgery, pelvic irradiation, or the use of luteinizing hormone-releasing hormone (LHRH) analogues. Because of the resistance of the ovary to aromatase inhibition (discussed above, see Fig. 56.1) aromatase inhibitors have traditionally been tested in postmenopausal patients. On the other hand, the activity of the very potent third-generation inhibitors makes it likely that these compounds will also inhibit ovarian steroidogenesis and, therefore, may be of use in the treatment of premenopausal women, although supporting clinical studies have not yet been reported.

Male Breast Cancer

Male breast cancer, although a rare condition, is frequently an estrogen-dependent tumor. Only anecdotal reports are available concerning the activity of aromatase inhibitors in this setting.

Future Perspectives in the Clinical Development of Aromatase Inhibitors

As discussed above, several aromatase inhibitors are now available for the treatment of breast cancer.71 The goals of clinical research with these agents were to obtain drugs that are convenient to administer at a dose that specifically inhibits aromatase without exerting other endocrine effects and without causing significant clinical toxicity. Unlike the case with other antitumor agents, our ability to precisely assay hormonal levels in clinical subjects makes it possible to determine the specificity and the optimal dose of an aromatase inhibitor that causes maximal estrogen suppression.

Future clinical trials with these promising agents must address several questions. Such questions include their role in the treatment of premenopausal women as discussed above, as well as their use as first-line therapy for metastatic hormone-dependent breast cancer. Aromatase inhibitors might also be considered as adjuvant therapy for breast cancer and may even have a role in the chemoprevention of this disease.

First Line Therapy

With the successful completion of phase III trials of newer generation of aromatase inhibitors in patients with metastatic breast cancer progressing on tamoxifen, clinical attention has now turned to the evaluation of these agents as first-line endocrine therapy. Several studies comparing anastrozole, letrozole, and exemestane with tamoxifen are either ongoing or planned. Only preliminary clinical data are available. It is likely, however, that in similar groups of well-selected patients, the new aromatase inhibitors will prove to have similar efficacy to each other and to tamoxifen.

Adjuvant and Neoadjuvant Therapy

The adjuvant use of antiestrogen therapy undoubtedly improves survival in patients with estrogen receptor–positive primary breast cancer. The only study of an aromatase inhibitor used as adjuvant therapy reported thus far employed the older agent aminoglutethimide. However, at least one large, international, multi-center trial comparing anastrozole with tamoxifen or the combination of the two agents as adjuvant treatment in postmenopausal women with estrogen receptor–positive breast cancer is approaching clinical maturity. Adjuvant trials with exemestane and letrozole are also in progress.74

It has been postulated that prolonged exposure of breast cancer cells to tamoxifen can induce a state of “estrogen supersensitivity”.75 Tamoxifen could then stimulate tumor growth as a result of its estrogen agonist properties. A recently initiated intergroup trial will test this concept as a new strategy of prolonged adjuvant endocrine therapy. In this study, postmenopausal patients completing 5 years of adjuvant therapy with tamoxifen will then be randomized to receive an additional 5 years of letrozole or placebo.

Neoadjuvant Therapy

In clinical practice, some elderly patients still initially present with locally advanced and often neglected large primary breast cancers. In this clinical setting, surgery is often not the optimal management, either because of the size of the tumor or the presence of comorbidities in this patient population. Tamoxifen has been used as neoadjuvant hormonal management of such patients. Preliminary data now show the marked activity of letrozole used as neoadjuvant endocrine therapy with resulting downstaging of large primary breast tumors to an operable status.76 Prospective randomized trials are now attempting to confirm these observations.


Estrogens are clearly carcinogenic, perhaps, because of their proliferative effects on normal breast epithelium as well as the genotoxic effects of certain estrogen metabolites. By lowering tissue levels of estrogen, aromatase inhibitors might block both initiation and promotion of breast cancer. Aromatase inhibitors might be ideal agents to investigate in the chemoprevention of breast cancer.

Coombes and associates have reported that 4-OHA prevents (NMU)-induced rat mammary carcinoma.77 Similar observations with other aromatase inhibitors and animal models suggest that inhibitors of estrogen biosynthesis can prevent breast cancer. Moreover, aromatase inhibitors would not be expected to induce endometrial carcinoma in women and, therefore, might be preferred to antiestrogens in the chemoprevention of human breast cancer.

Combination verses Sequential Therapy

A few clinical studies have attempted to combine different classes of endocrine agents, but there are no data to support this approach as being superior to the use of these agents in sequence to treat metastatic breast cancer. Furthermore, combinations of agents might lead to unfavorable pharmacologic interactions. In women with metastatic hormone-dependent breast cancer, a typical sequence of endocrine therapy would be the use of tamoxifen followed by an aromatase inhibitor in responding patients followed by a progestin as third-line therapy.77

Hormonal Resistance and Breast Cancer Biology

In clinical practice the sequential use of hormonal agents can produce long-term palliation of hormone-dependent breast cancer. Eventually, however, the problem of hormone resistance is encountered. The mechanisms by which tumors become resistant to hormones, in general, are only partially understood. Refractoriness to therapy with aromatase inhibitors is related not to the failure of these agents to suppress estradiol levels but rather to some other mechanism of hormone resistance.

Because of the development of two different classes of aromatase inhibitors, steroidal (or “irreversible” substrate-site type I) and nonsteroidal, (heme-binding, type II) inhibitors (see Table 56.2), the question has been raised concerning possible non–cross-resistance to the different inhibitors used to treat breast cancer. Preliminary reports in small clinical trials indeed suggest that some patients progressing on aminoglutethimide might subsequently respond to more potent aromatase inhibitors. Similar studies also report further responses in patients with tumor progression following treatment with competitive inhibitors who are then switched to the steroidal, mechanism-based inhibitors, such as formestane and exemestane.40,43,78 Lack of complete cross-resistance among the two classes of aromatase inhibitors would be of considerable clinical significance and would extend the utility of this class of agents. These preliminary data need confirmation by large, randomized clinical trials.

The paracrine production of aromatase, specific growth factors, and cytokines within the microenvironment of a breast tumor requires further study. Greater understanding of the biologic interaction of these factors could lead, for example, to the development of new therapeutic strategies.


In summary, recent and ongoing clinical studies of highly potent aromatase inhibitors have shown that it is possible to develop specific, nontoxic compounds, which reduce serum estradiol concentrations to undetectable levels in breast cancer patients and also significantly reduce the intratumoral levels of aromatase.71,75 These compounds are emerging as a valuable approach to the treatment of hormone-dependent breast cancer. Should the new aromatase inhibitors prove to effectively inhibit ovarian steroidogenesis as well as extraglandular and intratumor aromatase, then they may have a role in the treatment of other malignancies, such as endometrial cancer, granulosa cell tumors, melanoma, prostate cancer, and pancreatic carcinoma, as well as benign conditions, such as precocious puberty, uterine leiomyoma, endometriosis, and other hyperestrogenic states.


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