Emerging Role of Aromatase Inhibitors in the Treatment of Breast Cancer
Emerging Role of Aromatase Inhibitors in the Treatment of Breast Cancer
The hormone dependence of some forms of human breast cancer was first suggested by the pioneering work of Beatson in 1896. Subsequent refinement of this concept and description of the role of the estrogen receptor by Jensen et al led to an appreciation of the fundamental action of estrogen in mediating the differentiation and growth of primary and metastatic mammary carcinoma.
Hormone-dependent breast cancer is characterized by the presence of steroid hormone (estrogen and progesterone) receptors. Estrogen receptor (ER)-positive tumors tend to be more indolent in their clinical behavior and are more common in older women. Most important, when metastatic, this tumor subtype can be effectively managed by the sequential use of various hormonal manipulations.
Major endocrine ablative therapies, such as hypophysectomy and adrenalectomy, have been replaced by more elegant pharmacologic approaches. These approaches derive from our better understanding of the mechanisms of hormonal action, receptor physiology, and the biology of the autocrine growth control of breast cancer by in situ estrogen synthesis, as well as paracrine control, mediated by a variety of growth factors and their receptors.
Blockade of ER action by antiestrogen therapy with tamoxifen (Nolvadex) or other triphenylethylene derivatives, such as toremifene (Fareston) or droloxifene, is currently the best approach to the endocrine treatment of breast cancer in both the adjuvant and palliative settings. In patients whose disease progresses following antiestrogen therapy and who remain candidates for further endocrine therapy, however, new treatment strategies must be adopted. Since there is little evidence for non-cross-resistance among the currently available antiestrogens, there is no clinical advantage to be gained by switching therapy from one of these compounds to another.
Traditionally, progestins have been used as the second-line hormonal therapy in this clinical situation. The mechanism of action of progestins in this setting is complex and poorly understood. In contrast, the blockade of estrogen synthesis by agents that inhibit aromatase activity has now been well studied, and several new agents are available for clinical use. This paper will demonstrate that the new class of aromatase inhibitors should now be considered as an alternative to progestins for second-line hormonal therapy.
In postmenopausal women, the majority of circulating biologically active estrogens, including estrone and estradiol, are formed by the enzymatic conversion of androstenedione and testosterone secreted by the adrenal glands. This process of aromatization occurs at peripheral sites, such as adipose tissue, liver, and muscle. Another important target for the inhibition of aromatase activity is breast cancer tissue itself, since some tumors have been shown to be capable of the local synthesis of estrogens.
Aminoglutethimide was the first aromatase inhibitor to be widely tested in postmenopausal women with metastatic hormone-dependent breast cancer. Worldwide experience demonstrated that the regimen of aminoglutethimide and hydrocortisone was, indeed, very effective in producing clinical responses in women with ER-positive, advanced breast cancer.This regimen was associated with troublesome clinical toxicity, however. It also was not specific for aromatase inhibition, since levels of other cytochrome P450 synthesis-dependent hormones, including cortisol, aldosterone, and thyroid hormone, could be affected.
More recently, several nonsteroidal imidazole and triazole derivatives have been synthesized as competitive inhibitors of aromatase. These new compounds are potent and highly selective for aromatase inhibition. The newer aromatase inhibitors show promising clinical activity when used as second-line therapy for metastatic disease in postmenopausal women. Furthermore, these new drugs produce minimal side effects.
The specificity and potency of the new compounds were first demonstrated in a number of phase I and II trials that included careful measurement of steroid hormone levels in normal volunteers and postmenopausal women with breast cancer before and after treatment with both competitive and mechanism-based suicide-type steroidal inhibitors.[7-9]
Recently Approved Aromatase Inhibitors
Several large, randomized, phase III clinical trials of the new aromatase inhibitors have been reported recently, and the results of some of these pivotal trials were the basis for FDA approval of two of these agents. Most of these trials enrolled postmenopausal patients in whom disease had progressed during tamoxifen therapy but who were still deemed eligible for further hormonal treatment and had either measurable or evaluable metastatic disease. In many of the trials, the standard treatment was megestrol acetate (40 mg PO qid or 160 mg qd).
The results of two large, international, multicenter, prospective randomized trials comparing anastrozole (Arimidex), 1 or 10 mg, to megestrol acetate have been combined and show similar response rates of approximately 35% for both doses of anastrozole and megestrol acetate. However, in this pivotal trial, women receiving anastrozole experienced significantly less weight gain and overall fewer thromboembolic events, compared to patients treated with megestrol.
On the basis of these results, anastrozole, in a dose of 1 mg once daily, became the first aromatase inhibitor to be approved in the United States for the treatment of postmenopausal women with metastatic breast cancer. A recent follow-up of this study now shows an improved time to tumor progression and survival in women treated with anastrozole compared to megestrol acetate.
A trial of similar design comparing letrozole (Femara) to megestrol acetate reported response rates of 23.6% vs 16.4% and a trend toward a longer time to tumor progression favoring the aromatase inhibitor. In this study, letrozole was somewhat better tolerated than megestrol. In another trial, letrozole was compared to aminoglutethimide in a similar group of patients and was deemed to be more effective and less toxic. On the basis of these recent trials, letrozole, in a dose of 2.5 mg once daily, was the second aromatase inhibitor to gain FDA approval and is now being marketed with an indication similar to that for anastrozole.
Some in vitro laboratory studies and hormonal measurements in patients suggest that letrozole may produce a higher degree of aromatase inhibition than does anastrozole. The clinical significance of these findings is unknown and speculative.
Other Aromatase Inhibitors
Studies comparing vorozole to megestrol and aminoglutethimide have also been reported. These preliminary reports seem to show a therapeutic advantage for the aromatase inhibitor, but vorozole has not yet been approved for clinical use.
In another trial, fadrozole was compared to megestrol acetate and produced a similar response rate and median time to progression. Fadrozole has been compared to tamoxifen as first-line endocrine therapy in postmenopausal women with metastatic breast cancer, and the two agents produced similar clinical results. Since both anastrozole and letrozole are more potent and selective than fadrozole, it is unlikely that this agent will be developed further.
Exemestane is a nonsteroidal, specific, irreversible inhibitor of aromatase that is currently undergoing active clinical trials.