Aromatase Inhibitors as Adjuvant Therapy in Breast Cancer
Aromatase Inhibitors as Adjuvant Therapy in Breast Cancer
ABSTRACT: The aromatase inhibitors are regarded as standard approaches to first- or second-line endocrine therapy in women with hormoneresponsive metastatic breast cancer. Their efficacy and apparent lack of toxicity have led to their evaluation as adjuvant therapy. Although initial results with these agents in early breast cancer are promising, our collective long-term experience documenting tamoxifen’s benefits and our uncertainty about the long-term effects of aromatase inhibitors suggest that it is too early to recommend their routine use in the adjuvant setting. However, anastrozole is also a reasonable therapeutic option in the adjuvant setting, particularly in individuals with a contraindication to tamoxifen such as those with thromboembolic disease or those who develop breast cancer while receiving tamoxifen or raloxifene (Evista) therapy. Anastrozole (Arimidex) was recently approved by the Food and Drug Administration for the adjuvant treatment of postmenopausal women with hormone-receptor–positive early breast cancer. Ongoing trials are assessing the potential role of aromatase inhibitors in the adjuvant, neoadjuvant, and preventive settings.
The modest decline in breast cancer mortality in the United States in the late 1990s (3.4% annually) has been attributed to early detection strategies and effective adjuvant systemic therapy. Despite these promising statistics, the 15-year survival rate for breast cancer is still only about 60%. These data highlight the need for innovative therapies such as the new generation of aromatase inhibitors, including anastrozole (Arimidex), exemestane (Aromasin), and letrozole (Femara). These drugs specifically target the enzyme aromatase, in contrast to earlier aromatase inhibitors such as aminoglutethimide (Cytadren), which were less selective, less potent, and more toxic.
Currently, the use of tamoxifen for 5 years is regarded as standard treatment for postmenopausal women with early-stage hormone-responsive breast cancer. However, initial data from the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial suggest that anastrozole may be at least as effective as tamoxifen for postmenopausal women with estrogen- receptor (ER)-positive tumors.
In this article, we review our current understanding of the role of aromatase inhibitors in the adjuvant treatment of postmenopausal hormone- responsive breast cancer. The review will focus on (1) the function of aromatase inhibitors in breast cancer, (2) clinical trials with aromatase inhibitors in advanced breast cancer, (3) data from trials of aromatase inhibitors in the adjuvant setting including the recently published ATAC trial, (4) results from studies of aromatase inhibitors in the neoadjuvant setting, and (5) current recommendations about adjuvant use of aromatase inhibitors.
Aromatase Inhibitors in Breast Cancer
The enzyme aromatase is part of the cytochrome P450 superfamily. It is required for the peripheral conversion of androstenedione to estro gen, the final step in the estrogen biosynthesis pathway. Aromatase activity is more important in postmenopausal women than in their premenopausal counterparts because most estrogen is produced in the ovaries and regulated by gonadotropins in premenopausal women. In postmenopausal women, conversion of androgen to estrogen in peripheral tissues is the primary source of estrogen.
Aromatase is present in a number of important tissues in females including muscle, fat, skin, neural structures, and breast tissue. Elevated levels of both estrogen and aromatase have been demonstrated in malignant breast tissue, supporting a role for in situ production of estrogen in malignant breast cells. Extensive preclinical and clinical data show that estrogen increases the growth and proliferation of breast cancer cells, and estrogen deprivation leads to tumor regression.
Mechanisms of Action
Aromatase inhibitors use two distinct mechanisms to block the action of aromatase and thereby reduce estrogen production. Type I inhibitors such as exemestane and formestane (Lentaron) are androgen-like compounds that bind irreversibly to the substrate-complex, causing permanent inactivation of the enzyme.[8,9] This could potentially lead to prolonged estrogen deprivation even after the drug is cleared. These drugs are also known as aromatase inactivators. Type II inhibitors such as aminoglutethimide, letrozole, and anastrozole are nonsteroidal compounds that reversibly bind to the heme-iron component of the aromatase enzyme, thereby inhibiting the conversion of androgen to estrogen in an indirect fashion.
Aminoglutethimide, the first clinically available aromatase inhibitor, was introduced in the late 1970s for the second-line treatment of postmenopausal women with advanced breast cancer. The widespread use of this inhibitor was limited by its toxicity and lack of selectivity for the aromatase enzyme, leading to suppression of other steroidal synthetic pathways such as those for glucocorticoids and mineralocorticoids.
In 1993, 4-hydroxyandrostenedione, or formestane, became available as an intramuscular injection. It was more specific and associated with fewer systemic side effects but had to be given frequently and in large doses because of its extensive firstpass metabolism. In the mid- 1990s, a new generation of aromatase inhibitors including letrozole, anastrozole, and exemestane became available in the United States, and fadrozole was released abroad. These new drugs are administered orally and have long half-lives, enabling once-daily dosing.
All three aromatase inhibitors have been shown to almost completely suppress aromatase activity (97%-99%) in postmenopausal women, leading to a significant decrease in estrogen production within 7 days. Maximal estradiol suppression occurs 50% earlier in women taking anastrozole and letrozole compared to exemestane. Aminoglutethimide also suppresses aromatase activity in postmenopausal women by up to 85% but does not reduce estrogen levels to the same degree.[8,12-15] Of note, aromatase inhibitors have been shown to suppress estrogen alone in premenopausal women who are already receiving gonadotropin-releasing hormone agonists.[3,16,17]
The new aromatase inhibitors are also more selective and potent, resulting in decreased toxicity compared with aminoglutethimide, although type I steroidal inhibitors like exemestane can cause dose-related androgenic side effects. Neither anastrozole nor exemestane affects cortisol and aldosterone levels, but both can suppress sex hormone-binding globulin levels. Letrozole can decrease cortisol and increase both aldosterone and sex hormone-binding globulin levels. Whether any of these biochemical and pharmacologic differences translate into significant clinical differences remains to be seen.[3,8]
There are also differences in how the aromatase inhibitors interact with tamoxifen. The simultaneous use of aminoglutethimide and tamoxifen leads to a 70% decrease in tamoxifen concentrations. On the other hand, the combination of tamoxifen and letrozole results in a 40% reduction in plasma concentrations of letrozole.[ 20-21] Anastrozole does not seem to interact with tamoxifen when given in combination.[22,23] These results are important in the consideration of combined endocrine therapy.