Hormonal therapy remains an integral part of the management of breast cancer for most women. Tamoxifen(Drug information on tamoxifen) (Nolvadex) has been the hormonal agent of choice for women with estrogen-receptor- and/or progesterone(Drug information on progesterone)- receptor-positive tumors in both the adjuvant and metastatic disease settings. It has also demonstrated efficacy in the chemoprevention setting. Although tamoxifen has had a profound and positive impact on the management of breast cancer, the availability of the newer anti-aromatase agents offers the potential for improving the therapeutic index in women with breast cancer. In addition, these agents offer a new approach for consideration in chemoprevention of the disease.
Estrogen exposure has long been known to be a risk factor for breast cancer development. Early menarche, late menopause, and obesity in the postmenopausal setting (which is associated with high estrogen levels) are all associated with greater risk of breast cancer. Particularly striking in this regard are the data on surgically induced menopause from Trichopoulos et al, who found a 60% reduction in breast cancer risk in women so treated compared with those experiencing a natural menopause. Although they found the reduction greatest for women whose menopause was induced before age 35, reductions were also seen in women up to the age of 50 years.
Interference with estrogen action and reduction in estrogen production are two major approaches taken in the management of hormone-dependent breast cancer. The interference with estrogen action is best exemplified by the use of tamoxifen, where the mechanism of action is thought to be primarily related to competition with estrogen for the estrogen receptor, which results in decreased expression of estrogen-regulated genes. Reduction in estrogen production is exemplified by the use of ovarian ablation in premenopausal women and use of agents that inhibit the aromatase system in postmenopausal women.
Converting to Estrogen
In postmenopausal or castrated women, the major source of estrogen is the peripheral conversion of androstenedione, which is secreted by the adrenal gland, via aromatase, which is a complex of a cytochrome P450 hemoprotein and a flavoprotein, NADD (nicotinamide adenine dinucleotide diphosphate) cytochrome P450 reductase. Aromatization is the rate-limiting step in the conversion of androstenedione to estrone, which can subsequently be reduced to estradiol(Drug information on estradiol).
Adipose tissue contains substantial aromatase activity and is responsible for much of the peripheral conversion of androstenedione to estrone(Drug information on estrone). The breast, however, is also a site for this peripheral conversion, with obvious implications for breast cancer development. Miller and O’Neill examined aromatase activity in different quadrants of mastectomy specimens and found the activity was always higher in the quadrant associated with the tumor.
High Estradiol Levels
The concentration of estradiol in plasma is substantially lower in post-menopausal than in premenopausal women. Despite this differential, Pasqualini et al found that the levels of estradiol in breast cancer tissue were similar in premenopausal and postmenopausal women, and that the levels of estrone sulfate were significantly higher in the latter patients. Esteban et al, using immunohistochemical methodology, found that 15 (40%) of 38 breast cancers demonstrated significant immunoreactivity for aromatase. Utilizing an assay for aromatase activity that quantifies production of tritiated water release from 1ß-tritiated- androstenedione, Lipton et al found measurable aromatase activity in 69% of 113 breast cancers.
The finding of relatively high estradiol levels in breast cancers in postmenopausal women and the identification of aromatase activity raises the question of the relative importance of in situ aromatization vs enhanced uptake from plasma. An intriguing study addressing this issue was performed by Yue et al, who developed a model in which aromatase- and sham-transfected MCF-7 cells were inoculated into ovariectomized nude mice and then androstenedione was administered. Heterotransplants in which aromatase-transfected MCF-7 cells were implanted in one flank and sham-transfected cells in the other flank demonstrated that the tumor weight was 7.6-fold larger and the estradiol concentration 3- to 4-fold higher in the aromatase-transfected tumors.
Yue also examined the impact of estradiol administration by silastic implants and androstenedione by injection in ovariectomized mice with implantation of aromatase-transfected MCF-7 cells. The estradiol administration always produced lower tumor growth rates and lower estradiol levels than androstenedione, supporting the position that in situ aromatization plays a major role in determining the tissue estradiol levels. An additional consideration is that, whereas circulating estrogens(Drug information on estrogens) may be bound to sex hormone binding globulins, this would not be the case in estrogens produced in situ and acting in a paracrine or intracrine fashion.
The three generations of aromatase inhibitors are listed in Table 1. Steroidal aromatase inhibitors, also known as type I, interact with the substrate binding site on the peptidic moiety of the enzyme complex in an irreversible manner, which has led to their designation as aromatase inactivators. Nonsteroidal aromatase inhibitors, also known as type II, coordinate with the iron atom of the cytochrome P450 moiety of the enzyme in a reversible manner. The striking change that has occurred with the advent of the third-generation aromatase inhibitors is the increased potency and increased specificity, with activity confined to aromatase inhibition, over earlier generations. Additionally, these agents have markedly improved tolerability. Of particular importance is that the clinical antitumor efficacy has been shown to be improved with third-generation agents.
Gershanovich et al performed a prospective randomized trial in postmenopausal women with advanced breast cancer comparing letrozole(Drug information on letrozole) (Femara) with aminoglutethimide (Cytadren), and found that letrozole resulted in superior time to disease progression, time to treatment failure, and overall survival, and was associated with fewer side effects.
Large randomized phase III trials comparing megestrol(Drug information on megestrol) acetate with each of the third-generation aromatase inhibitors resulted in replacing megestrol acetate (Megace) as the treatment of choice in women with advanced breast cancer who have failed tamoxifen.[10-13]
First- and Second-Generation Inhibitors
Several, albeit relatively small, randomized clinical trials have been performed comparing first- and second-generation aromatase inhibitors with tamoxifen as first-line hormonal therapy in the advanced breast cancer setting. In a study by Smith et al, 117 patients were randomly assigned to receive either tamoxifen or aminoglutethimide, and the two treatments were associated with equal objective response rates (30%) and median durations of response (15 months). Although toxicity was greater with aminoglutethimide, the level of efficacy appeared equal between the two agents.
Formestane (4-OHA, 4-hydroxy-androstenedione) was compared with tamoxifen in 348 evaluable patients with objective response rates of 33% and 37%, median durations of response of 15 and 20 months, and overall survivals of 35 and 38 months, respectively. However, time to disease progression and time to treatment failure significantly favored tamoxifen.
Fadrozole (CGS 16949A) was compared with tamoxifen in 212 evaluable patients. Response rates were 20% and 27%, respectively, and mean times to treatment failure were 6.1 and 8.5 months, respectively (P = .09). Thus, although aromatase inhibitors were shown to have activity, tamoxifen remained the hormonal agent of choice in the first-line setting.
Information relating to the value of third-generation aromatase inhibitors relative to tamoxifen is beginning to appear; the most mature data relate to anastrozole(Drug information on anastrozole) (Arimidex). Buzdar et al recently presented the results of two randomized double-blind studies (T27, T30) that compared anastrozole and tamoxifen as first-line therapy for advanced breast cancer. This large study involved 1,021 patients who were estrogen-receptor positive and/or progesterone-receptor positive, or who had an unknown receptor status. The complete response and partial response rates were similar (anastrozole 29%, tamoxifen 27%), with median times to treatment failure of 8.5 and 7.0 months, respectively.
Of particular interest is that the progression-hazard ratio had a lower bound of 1.0, indicating that anastrozole was at least equivalent to tamoxifen in this regard. In subset analysis, in the 57.7% of patients known to be hormone-receptor positive, a significantly longer time to progression was identified for the anastrozole group. From a toxicity standpoint, fewer thromboembolic events and vaginal bleeding were seen with anastrozole.
Other Aromatase Inhibitors
Less information is available with the other aromatase inhibitors. A large randomized study involving more than 900 patients comparing letrozole with tamoxifen has completed accrual. Results should be forthcoming. A phase III study of exemestane(Drug information on exemestane) (Aromasin) vs tamoxifen is being conducted as an extension of a randomized phase II trial that had demonstrated encouraging results regarding exemestane efficacy.