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Aromatase Inhibitors in the Treatment and Prevention of Breast Cancer

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Aromatase Inhibitors in the Treatment and Prevention of Breast Cancer REVIEW ARTICLE Aromatase Inhibitors in the Treatment and Prevention of Breast Cancer By Paul E. Goss and Kathrin Strasser Purpose: The purpose of this article is to provide an fore considered established second-line hormonal overview of the current clinical status and possible agents. Currently, they are being tested as first-line future applications of aromatase inhibitors in breast therapy in the metastatic, adjuvant, and neoadjuvant cancer. settings. Preliminary results suggest that the inhibitors Methods: A review of the literature on the third- might displace tamoxifen as first-line treatment, but generation aromatase inhibitors was conducted. Some further studies are needed to determine this. data that have been presented but not published are Conclusion: The role of aromatase inhibitors in pre- included. In addition, the designs of ongoing trials with menopausal breast cancer and in combination with aromatase inhibitors are outlined and the implications chemotherapy and other anticancer treatments are ar- of possible results discussed. eas of future exploration. The ongoing adjuvant trials Results: All of the third-generation oral aromatase will provide important data on the long-term safety of inhibitors—letrozole, anastrozole, and vorozole (non- aromatase inhibitors, which will help to determine their steroidal, type II) and exemestane (steroidal, type I)— suitability for use as chemopreventives in healthy have now been tested in phase III trials as second-line women at risk of developing breast cancer. treatment of postmenopausal hormone-dependent J Clin Oncol 19:881-894. © 2001 by American breast cancer. They have shown clear superiority com- Society of Clinical Oncology. pared with the conventional therapies and are there- EVERAL CLASSES OF endocrine agents that antago- In this article, the rationale for the use of aromatase S nize the effects of estrogen are useful in the treatment inhibitors in breast cancer treatment, their mechanism of of estrogen receptor (ER)–positive breast cancer.1 For action, and preclinical test systems used in their evaluation example, selective estrogen receptor modulators (SERMs) are briefly reviewed. The current clinical status of third- and pure antiestrogens antagonize ER function by binding generation aromatase inhibitors is discussed and ongoing competitively to the receptor. Steroidal antiestrogens addi- clinical trials of these agents are described. Possible future tionally reduce ER concentration by inducing estrogen applications of aromatase inhibitors in the treatment and receptor degradation.2 Surgical, medical, and radiation- prevention of breast cancer are also outlined. induced ovarian ablation and aromatase inhibitors antago- There may be specific biologic and pharmacologic rea- nize the action of estrogen by reducing its levels both in the sons for giving aromatase inhibitors after tamoxifen. On the circulation and in normal and malignant breast tissue. Aromatase (estrogen synthetase) inhibitors have become the established second-line treatment for ER-positive met- From the Division of Hematology/Oncology, Princess Margaret astatic breast cancer after the SERM tamoxifen. The third- Hospital, Toronto, Ontario, Canada. generation aromatase inhibitors are currently being com- Submitted April 27, 2000; accepted September 18, 2000. pared with tamoxifen in first-line metastatic, adjuvant, and Over the past 10 years, P.E.G. has received industry funding for investigator-initiated clinical and laboratory studies of aromatase neoadjuvant settings. Should they prove superior to tamox- inhibitors as well as honoraria for presenting papers or acting in a ifen in terms of disease response, toxicity, and, most scientific advisory capacity. Support of this nature has been received importantly, patient survival, they might replace tamoxifen from manufacturers of all of the third-generation inhibitors that have as first-line endocrine therapy. Based primarily on a supe- been tested and/or approved for use, including vorozole (Janssen Ortho rior side effect profile, anastrozole has recently been ap- Inc, North York, Toronto, Ontario), letrozole (Novartis Pharmaceuti- cals Canada Inc, Dorval, Quebec), exemestane (Pharmacia & Upjohn, proved as first-line therapy of metastatic breast cancer in Mississauga, Ontario), anastrozole (AstraZeneca, Mississauga, On- several countries. The efficacy and excellent tolerability of the tario, Canada), and liarozole (Janssen Ortho). K.S. has not received newer aromatase inhibitors in the treatment of breast cancer any financial support from industry. might lead to their use as chemopreventives in healthy women Address reprint requests to Paul E. Goss, MD, PhD, Division of Hematology/Oncology, Princess Margaret Hospital, 610 University considered at significant risk of developing breast cancer. To Ave, Toronto, ON M5G 2M9, Canada; email: [email protected]. this end, studies are underway to investigate their ability to © 2001 by American Society of Clinical Oncology. alter surrogate markers of breast cancer risk. 0732-183X/01/1903-881 Journal of Clinical Oncology, Vol 19, No 3 (February 1), 2001: pp 881-894 881 882 GOSS AND STRASSER other hand, the inhibitors may be more effective than therapy in premenopausal women merits further investiga- tamoxifen if given as first-line treatment. For these reasons tion at standard and higher doses. and also because tamoxifen is the current standard of care as Increasingly, the female breast has itself been recognized first-line hormonal therapy for metastatic disease, as adju- as another important site of estrogen production. Stromal vant therapy and as an approved chemopreventive in the cells in breast adipose tissue produce estrogen that is United States, we have structured this review as aromatase biologically active in both a paracrine and an autocrine inhibitors after tamoxifen, as first-line therapy, and in manner.13 This is probably responsible for the observation combination with other agents. that estrogen concentrations in the healthy breasts of post- menopausal women are unexpectedly higher (four- to six- INHIBITING ESTROGEN SYNTHESIS AS A fold) than in serum and similar to those in premenopausal THERAPEUTIC TARGET women.14 In addition up to 70% of breast cancer cells have Aromatase is the enzyme complex responsible for the been shown to synthesize estrogen as a result of intracellular final step in estrogen synthesis, viz the conversion of the aromatase expression.15-18 This explains why aromatase androgens androstenedione and testosterone to the estrogens expression and activity are higher in breast tumors than in estrone (E1) and estradiol (E2). There are substantial data peritumoral fat and in tumor-bearing quadrants of the breast showing that estrogen promotes and probably initiates compared with those without tumors.19-23 There is increas- breast cancer.3 Inhibiting estrogen at the source of its ing evidence that this local estrogen production may play a synthesis is therefore a logical target of breast cancer major role in tumor proliferation.24-27 Intratumoral aro- treatment. matase has been linked to response to the aromatase The sites of estrogen synthesis include the ovaries of inhibitor aminoglutethimide18,28 but surprisingly not to premenopausal women; extragonadal sites such as fat, estrogen receptor expression.18,29 Despite similar depletion muscle, and skin; normal breast stromal cells; and breast of serum estrogen levels with the current third-generation tumor tissue. After ovarian failure, estrogen is synthesized aromatase inhibitors, variability in patient outcome on these in peripheral tissues and circulates at low, relatively non- drugs could be attributable to differences in inhibition of fluctuating levels.4,5 This peripheral aromatization in post- local estrogen synthesis. menopausal women is almost completely inhibited by single-agent administration of any of the third-generation MODELS FOR EVALUATING AROMATASE INHIBITORS inhibitors.6,7 In contrast, there is a barrier to using aromatase Potency and Reversibility inhibitors as monotherapy in premenopausal women. First, high levels of androstenedione compete initially with the For in vitro assessment of aromatase inhibitory capabil- inhibitors as substrate for the enzyme complex and conse- ity, microsomal preparations from rat ovaries or from quently estrogen synthesis is not completely blocked.8-10 human placenta are used.30,31 Inhibition of the enzyme and Second, suppression of estrogen results in a reflex increase potency of the inhibitor are determined by the amount of in gonadotrophin levels, provoking an ovarian hyperstimu- tritiated water released in the assay. By washing the lation syndrome, which causes a steep increase of aromatase microsomal preparations and measuring residual inhibition in the ovary and in turn overcomes, at least in part, the of aromatase, the inhibitor can be classified as reversible or initial blockade to estrogen synthesis by the inhibitor.11 irreversible. However, although both type I (steroidal) and type II Depletion of serum estrogen levels has been used as a (nonsteroidal) inhibitors compete initially with the androgen measure of the potency of aromatase inhibitors in blocking precursors for the enzyme, the type I inhibitors subsequently estrogen synthesis in peripheral tissues. However, using inactivate the enzyme irreversibly, thus being referred to as traditional assays, suppression below the detection limit has suicide inhibitors. Therefore, with ongoing exposure to type been noted with all of the third-generation
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