Emerging Role of Aromatase Inhibitors in the Treatment of Breast Cancer

Transcription

1 Emerging Role of Aromatase Inhibitors in the Treatment of Breast Cancer Review Article [1] March 02, 1998 By Harold A. Harvey, MD [2] The new generation of potent steroidal and nonsteroidal inhibitors of the enzyme aromatase act by decreasing estrogen production throughout the body in postmenopausal women. The most potent of these agents may also inhibit estrogen synthesis within metastatic breast cancer tissue. The hormone dependence of some forms of human breast cancer was first suggested by the pioneering work of Beatson in 1896.[1] 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.[2] 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 Major endocrine ablative therapies, such as hypophysectomy and adrenalectomy, have been replaced by more elegant pharmacologic approaches.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. Current Hormonal Approaches 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.[3] 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.[4] 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. Importance of Aromatase 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.[5] Development of Aromatase Inhibitors 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.[6]this regimen was associated with Page 1 of 5

2 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. Comparative Trials 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.[10] 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.[11] 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.[12] In another trial, letrozole was compared to aminoglutethimide in a similar group of patients and was deemed to be more effective and less toxic.[13] 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.[14] Other Aromatase Inhibitors Studies comparing vorozole to megestrol and aminoglutethimide have also been reported.[15] 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.[16] 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.[17] 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. Selection of Patients Extensive clinical experience in breast cancer management has shown that the selection of patients who are ideally suited for hormonal therapies can be reliably based on a consideration of a number of clinical parameters. These include the presence of both estrogen and progesterone receptors in the tumor, a long disease-free interval, patient age, absence of rapidly progressing or visceral dominant disease, and prior response to other hormonal therapies. Page 2 of 5

3 The same criteria have now been shown to apply to the selection of patients for treatment with the new aromatase inhibitors. It has been speculated that the ability to assess aromatase content in individual tumors (eg, by immunohistochemistry) may help identify patients who are most likely to respond specifically to aromatase inhibitors. The fact that the expression of aromatase activity in some metastatic lesions does not always correlate with the presence of ERs also suggests the possibility of activity of aromatase inhibitors in patients who do not respond to other hormones.[18] None of these hypotheses has been rigorously tested, however. To date, there is no clinical evidence to support the use of aromatase inhibitors, even the new potent ones, in premenopausal patients. In the future, measurement of other tumor parameters, such as expression of Her-2/neu and p53, may prove useful in predicting the state of hormonal resistance and, therefore, the lack of response to conventional endocrine therapies, including aromatase inhibitors.[19] Sequence of Therapy Given the increasing number of agents available for hormone-dependent breast cancer, the clinician must decide on an optimal sequence for their use. Sequential therapy of these palliative modalities is preferable, since no clinical data support the use of combined hormonal therapies outside of an investigational protocol. In the premenopausal patient, ovarian ablation, luteinizing hormone-releasing hormone (LHRH) analogs, and tamoxifen produce similar clinical results in metastatic disease. In the postmenopausal patient with hormone-dependent breast cancer, antiestrogens remain the mainstay of endocrine therapy. Tamoxifen and related compounds, such as toremifene and droloxifene, have similar activities. Choice among these agents must be based on clinical experience and the degree of concern for side effects in individual patients. There is little evidence to support crossover treatment, for example, switching from tamoxifen to toremifene or vice versa, in the face of disease progression. In a patient whose disease has progressed > 1 year after completing adjuvant tamoxifen therapy, on the other hand, resumption of therapy with an antiestrogen is probably worthwhile. In patients whose disease is refractory to antiestrogen therapy but who are still likely to have hormone-responsive metastases, treatment with an aromatase inhibitor should be initiated, in preference to the traditional approach of using megestrol acetate. No data support switching such patients from anastrozole to letrozole or vice versa. Progestin therapy probably should now be reserved for third-line therapy in patients whose disease progresses after response to aromatase inhibitors. Conclusions The aromatase inhibitors are an important class of agents with a well-understood mechanism of action in the treatment of breast cancer in postmenopausal women; namely, inhibition of estrogen biosynthesis. The newly approved compounds anastrozole and letrozole are potent and highly selective anastrozole inhibitors, are administered orally once daily, do not require coadministration of glucocorticoids, and are free of estrogenic activity. Randomized clinical trials show that both anastrozole and letrozole are well tolerated and do not cause undesired weight gain or significant thromboembolic side effects. Both agents are active against metastatic disease in patients who no longer respond to tamoxifen. Aromatase inhibitors are recommended as second-line palliative hormonal therapy in women with hormone-dependent breast cancer. These agents have not been tested in premenopausal patients. Clinical trials are currently comparing aromatase inhibitors to antiestrogen as first-line endocrine therapy. Studies of their possible roles as adjuvant therapy or chemoprevention for breast cancer are also being planned. The introduction of these new drugs affords patients and clinicians expanded options for securing good quality of life and palliation of advanced hormone-dependent breast cancer. References: 1. Beatson G: On the treatment of inoperable cases of carcinoma of the mammal. Lancet 2: , Evans RM: The steroid and thyroid hormone receptor family. Science 240: , Page 3 of 5

4 3. Forbes JF: The control of breast cancer: The role of tamoxifen. Semin Oncol 24(suppl 1):5-19, Harvey HA: Aromatase inhibitors in clinical practice: Current status and a look to the future. Semin Oncol 23(4;suppl 9):33-38, Santner SJ, Pauley RJ, Tait L, et al: Aromatase activity and expression in breast cancer and benign breast tissue stromal cells. J Clin Endocrinol Metab 82(1): , Santen RJ, Samojlik E, Lipton A, et al: Kinetic hormonal and clinical studies with aminoglutethimide in breast cancer. Cancer 39: , Lipton A, Demers LM, Harvey H, et al: Letrozole (CGS 20267): Phase I study of a new potent oral aromatase inhibitor in breast cancer. Cancer 75(8): , Demers LM: Effects of fadrozole (CGS 16949A) and letrozole (CGS 20267) on the inhibition of aromatase activity in breast cancer patients. Breast Cancer Res Treat 30(1):95-102, Masamura S, Aldercreutz H, Harvey HA, et al: Aromatase inhibitor development for treatment of breast cancer. Breast Cancer Res Treat 33(1):19-26, Buzdar A, Jonat W, Howell A, et al: Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: Results of overview analysis of two phase III trials. J Clin Oncol 14(7): , Buzdar A, Jonat W, Howell A, et al: Significant improved survival with Arimidex (anastrozole) versus megestrol acetate in postmenopausal advanced breast cancer: Updated results of two randomized trials (abstract). Proc Am Soc Clin Oncol 16:156a, Dombernowski P, Smith I, Falkson G, et al: Letrozole, a new oral aromatase inhibitor for advanced breast cancer: Double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 16: , Marty M, Gershanovich M, Campos B, et al: Letrozole, a new, potent, selective aromatase inhibitor superior to aminoglutethimide in postmenopausal women with advanced breast cancer previously treated with antiestrogens (abstract). Proc Am Soc Clin Oncol 16:156a, Demers LM, Lipton A, Harvey HA, et al: The efficacy of CGS (letrozole) in suppressing estrogen biosynthesis in patients with advanced stage breast cancer. J Steroid Biochem Mol Biol 44(4-6): , Goss P, Wine E, Tannock I, et al: Vorozole versus Megace in postmenopausal patients with metastatic breast carcinoma who had relapsed following tamoxifen (abstract). Proc Am Soc Clin Oncol 16:156a, Buzdar AU, Smith R, Vogel C, et al: Fadrozole HCl (CGS 16949A) vs megestrol acetate treatment of postmenopausal patients with metastatic breast carcinoma: Results of two randomized double blind controlled multiinstitutional trials. Cancer 77(12): , Thurliman S, Beretta K, Bacchi M, et al: First line fadrozole hydrochloride vs tamoxifen in advanced breast cancer: Prospective randomized study (abstract). Proc Am Soc Clin Oncol 14:98a, Lipton A, Santner SJ, Santen RJ, et al: Aromatase activity in primary and metastatic human breast cancer. Cancer 59: , Leitzel K, Teramoto Y, Konrad K, et al: Elevated serum c-erb-2 antigen levels and decreased response to hormone therapy of breast cancer. J Clin Oncol 13(5): , Page 4 of 5

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