Aromatase inhibitors, in breast cancer

Smith IE, Dowsett M (2003) Aromatase inhibitors in breast cancer. N Engl J Med 348 2431-2442... 

Mokbel K. The evolving role of aromatase inhibitors in breast cancer. Int J Clin Oncol 2002 7(5) 279-83. 

Nishihori T, Choi J, DiGiovanna MP, Thomson JG, Kohler PC, McGum J, Chung GG. Carpal tunnel syndrome associated with the use of aromatase inhibitors in breast cancer. Clin Breast Cancer 2008 8(4) 362-5. 

Lake DE, Hudis C. Aromatase inhibitors in breast cancer an update. Cancer Control 2002 9 490-8. 

Santen, R. J. and Yue, W. 1999. The potential of aromatase inhibitors in breast cancer prevention. Endocrinol. Relat. Cancer 6 235 3. 

Brueggemeier, R.W, (2002). Aromatase inhibitors in breast cancer therapy. Expert Rev. Anticancer Ther. 

Despite the significant benefit that tamoxifen has bestowed on breast cancer patients, the third-generation aromatase inhibitors are rapidly replacing tamoxifen as the first-Une treatment for breast cancers. In this chapter, focus will be given to three representative small-molecule aromatase inhibitors for breast cancer exemestane (1, Aromasin ), anastrozole (2, Arimidex ), and letrozole (3, Femara ). 

Anastrazole is a nonsteroidal, type H, aromatase inhibitor that is 200 times more potent than aminoglutethimide. It is eliminated primarily via hqDatic metabolism, has a terminal half life of 50 h with steady state concentrations achieved approximately 10 days with once daily dosing regimens. It is administered orally at a dose of 1 mg/day that achieves near maximal aromatase inhibition and hence estrogen suppression in breast cancer patients. No effect on adrenal steroidogenesis has been observed at up to ten times the daily recommended dose. When used in the metastatic setting, anastrozole has been shown... 

Anastrozole is a selective nonsteroidal aromatase inhibitor that lowers estrogen levels. The pharmacokinetics of anastrozole demonstrate good absorption, with hepatic metabolism the primary route of elimination and only 10% excreted unchanged by the kidney. The elimination half-life is approximately 50 hours. Anastrozole is used for the adjuvant treatment of postmenopausal women with hormone-positive breast cancer and in breast cancer patients who have had disease progression following tamoxifen. Side effects include hot flashes, arthralgias, osteoporosis/bone fractures, and thrombophlebitis. 

In postmenopausal women, recently reported evidence supporting the use of aromatase inhibitors in the adjuvant setting is intriguing and may usurp the role of tamoxifen. Three different approaches to therapy have been undertaken with these new agents (1) direct comparison with tamoxifen for adjuvant hormonal therapy, (2) sequential use after 5 years of adjuvant tamoxifen therapy, and (3) sequential use after 2 to 3 years of adjuvant tamoxifen. Based on results of several studies, it has been concluded that therapy for postmenopausal women with ER-positive breast cancer should include an aromatase inhibitor.27,47 It is still unclear if the aromatase inhibitor should be used instead of tamoxifen or sequentially after receiving tamoxifen for 2 to 5 years.27 Concerns surrounding loss of bone density, changes in blood lipids, and cardiac and vascular disease require further study.27... 

The increasing clinical importance of tamoxifen in the 1980s prompted development of drugs that indirectly target the estrogen receptor, for example the aromatase inhibitor anastrozole (ARIMIDEX ), a selective inhibitor of estrogen biosynthesis [28]. Progress in treatment of hormone-dependent prostate cancer followed advances in breast cancer, with demonstration that... 

Several other aromatase inhibitors are undergoing clinical trials in patients with breast cancer. Fadrozole is an oral nonsteroidal (triazole) inhibitor of aromatase activity. These compounds appear to be as effective as tamoxifen. In addition to their use in breast cancer, aromatase inhibitors have been successfully employed as adjuncts to androgen antagonists in the treatment of precocious puberty and as primary treatment in the excessive aromatase syndrome. 

Nabholtz JM. Long-term safety of aromatase inhibitors in the treatment of breast cancer. Ther Clin Risk Manag 2008 4(l) 189-204. 

This study has again confirmed that endometrial problems can be induced by tamoxifen early in the course of treatment and that these problems do not arise with aromatase inhibitors, which may actually reduce the endometrial changes induced by tamoxifen. The idea that the new oral aromatase inhibitors might well replace tamoxifen in breast cancer was tentatively advanced in SEDA-26 (p. 445) and has now been supported by some of the material cited above, as well as by a panel consensus (25). Citing efficacy and safety data on anastrozole, exemestane, and letrozole, the authors concluded that third-generation aromatase inhibitors may be considered first-line therapy of hormone-receptor-positive advanced breast cancer in postmenopausal women and may also be used for preoperative therapy of breast cancer. 

Berry J. Are all aromatase inhibitors the same A review of controlled clinical trials in breast cancer. 

Aromatase inhibitors serve to eliminate ex-traovarian synthesis of estrogens in breast cancer patients. This can be achieved effectively only in postmenopause because, as an FSH-dependent enzyme, ovarian aromatase is subject to feedback regulation of female Luellmann, Color Atlas of Pharmacology 2005 Thieme All rights reserved. Usage subject to terms and conditions of license. 

Brodie, A.M. (1993) Aromatase. its inhibitors and their use in breast cancer treatment. Pharmacol. 77ter..60. 501-515. 

Bajetta E, Zilembo N, Bichisao E. Aromatase inhibitors in the treatment of postmenopausal breast cancer. Drugs Aging 1999 lS 271-83. 

Robertson J, Lee D. Static disease of long duration (greater than 24 weeks) is a important remission criterion in breast cancer patients treated with the aromatase inhibitor Arimadex (anastrozole) (Meeting abstract). Breast Cancer Res Treat 1997 46 214. 

Stein, R.C., M. Dowsett, J. Davenport, A. Hedley, H.T. Ford, J.-C. Gazet et al. (1990). Preliminary study of the treatment of advanced breast cancer in postmenopausal women with the aromatase inhibitor CGS 16949A. Cancer Res. 50, 1381-1384. 

Geisler, J., N. King, G. Anker, G. Omati, E. Di Salle, PE. Lonning et al. (1998). In vivo inhibition of aromatization by exemestane, a novel irreversible aromatase inhibitor, in postmenopausal breast cancer patients. Clin. Cancer Res. 4, 2089-2093. 

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