Aromatase Inhibitors in Breast Cancer: An Update

Diana E. Lake, MD, Clifford Hudis, MD


Cancer Control. 2002;9(6) 

In This Article

Abstract and Introduction

Background: Tamoxifen has been the endocrine treatment of choice for patients with breast cancer. The development of selective aromatase inhibitors has offered an alternative management approach for patients in whom a hormonal approach is indicated.
Methods: The authors reviewed reports in which aromatase inhibitors were compared with tamoxifen for the treatment of metastatic disease, as well as information pertinent to their use as adjuvant therapy.
Results: Both nonsteroidal (anastrozole and letrozole) and steroidal (exemestane) aromatase inhibitors for metastatic disease appear to provide superior efficacy and a better toxicity profile in first-and second-line treatment of metastatic disease than tamoxifen. Early results from the ATAC trial suggest anastrozole is superior to tamoxifen for disease-free survival, particularly in receptor-positive patients, and in reducing the incidence of contralateral breast cancer.
Conclusions: Aromatase inhibitors have important roles in optimal management of postmenopausal patients with hormone-responsive metastases in both the adjuvant and advanced-disease settings.

Endocrine therapy is the oldest, safest, and best-established systemic treatment for breast cancer, with utility in all stages of disease. Initially used to treat metastatic disease, it later became a critical component of adjuvant and neoadjuvant treatment.[1] Most recently, hormonal therapies have demonstrated a role in preventing recurrence of noninvasive disease and in preventing breast cancer outright.[2] The mechanisms of action of endocrine therapies are threefold: they may lower the estrogen level in the tumor (oophorectomy, aromatase inhibitors), they may modulate estrogen receptors (SERMS [tamoxifen, toremifene]), or they may modulate the estrogen receptor (ER) with pure agonist activity, eg, ER down-regulator (fulvestrant). Although high-dose estrogens, progestins, and androgens have activity against ER+ tumors, the exact mechanism of action is unclear. This article focuses on recent developments in the use of aromatase inhibitors and reviews their roles in the management of breast cancer.

In spite of the numerous choices in endocrine therapies, tamoxifen has remained the "gold standard" of first-line hormonal therapy in patients who have tumors expressing hormone receptors and who have had either no prior tamoxifen exposure or a long hiatus between adjuvant tamoxifen and the metastatic presentation. Tamoxifen was initially approved in the 1970s as treatment for metastatic breast cancer,[3] and in 1986, it was approved for adjuvant therapy in post-menopausal women with node-positive breast cancer. In 1990, tamoxifen received approval as adjuvant therapy in pre-and post-menopausal women with node-negative disease.[4] In the 1990s, it was demonstrated to be effective in breast cancer prevention and in the treatment of ductal carcinoma in situ.[5] Tamoxifen has been available for more than 20 years, and through multiple clinical trials, we have defined the population that benefits from its use, the long-term toxicity profile, and a standard dose and schedule.

Since virtually all patients with metastatic disease will eventually progress on tamoxifen, additional hormonal treatments are needed. Historically, nonselective aromatase inhibitors offered an option, but their toxicity was limiting and a progestin (megestrol acetate) was frequently employed following tamoxifen. The recent development of selective aromatase inhibitors has changed the options and approach for patients in whom treatment with tamoxifen has failed.

Aromatase inhibitors lower the level of estrogen in the tumor. In postmenopausal women, the primary estrogen source is derived from conversion of androstenedione (produced by the adrenals) to estrone and estradiol in the peripheral tissues, including skin, adipose tissue, and breast. Because premenopausal women have such robust estrogen production in the ovaries, these agents are not effective in these women. The enzyme responsible for the conversion is aromatase. Aromatase inhibitors block the conversion of androstenedione to estrone and testosterone to estradiol (Fig 1). Earlier aromatase inhibitors also affected adrenal corticosteroidal metabolism, resulting in marked toxicities. Currently, three selective aromatase inhibitors are available in the United States that offer significant safety advantages over their nonselective predecessors. These new agents are divided into two categories: steroidal/irreversible and nonsteroidal/ reversible inhibitors of estrogen synthesis. The nonsteroidal aromatase inhibitors are anastrozole and letrozole, and the steroidal compound is exemestane (Fig 2). Both classes reduce circulating estrogen to 1% to 10% of pretreatment levels.[6] Issues involving the indications for aromatase inhibitors in the treatment of breast cancer concern their roles in adjuvant therapy, treatment of metastases, and prevention.

Third-generation aromatase inhibitors: mechanism of action.

Structures of aromatase inhibitors. From Goss PE, Strasser K. Aromatase inhibitors in the treatment and prevention of breast cancer. J Clin Oncol. 2001;19:881-894.

It is important to recognize whether the aromatase inhibitor that is chosen for treatment is of a steroidal or nonsteroidal nature because there is a relative lack of cross-resistance between these two classes; clinical benefits may occur when a nonsteroidal aromatase inhibitor is prescribed following a steroidal agent, and vice versa. There is benefit from anastrozole given after exemestane[7] and also from exemestane given after anastrozole.[8]


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