Aromatase inhibitor postmenopausal breast cancer

In a prospective study in 77 consecutive women with postmenopausal breast cancer scheduled to start endocrine treatment for breast cancer, using either tamoxifen or an aromatase inhibitor tamoxifen treatment significantly increased endometrial thickness and uterine volume after 3 months (24). In additional, tamoxifen induced endometrial cysts and polyps and increased the size of pre-existing fibroids. In contrast, aromatase inhibitors did not stimulate endometrial growth and were not associated with endometrial pathology. Furthermore, they reduced endometrial thickness and uterine volume in patients who had previously taken tamoxifen. 

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

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. 

Mode of action aromatase inhibitor estrogen synthesis ° Use estrogen-dependent, postmenopausal breast cancer... 

Anastrozole (Fig. 46.11) is a potent and highly selective, nonsteroidal aromatase inhibitor utilized in the treatment of advanced breast cancer that is hormone-responsive. It is considered to be second-line therapy (after tamoxifen) in the treatment of postmenopausal breast cancer. Anastrozole. a benzyltriazole derivative, competes with the natural substrate for binding to the active site of the aromatase. The mechanism of enzyme inhibition resides in the coordination of the triazole ring with the heme iron atom of the aromatase enzyme complex (161,162). This coordination ultimately prevents aromatization of androgens into estrogens and, therefore, deprives the tumor of estrogen. This effect is reversible. In the presence of anastrozole. estradiol levels are reduced to undetectable levels, with no adverse effects on levels of any other hormone, including cortisol and aldosterone. 

Exemastane is a steroid-based, irreversible aromatase inhibitor that is approved for the treatment of estrogen-dependent tumors and postmenopausal breast cancer. It also has been ... 

Aromatase inhibitors are used to treat postmenopausal breast cancer. Two prime metastasis sites for breast cancer are the Inngs and bones. Negative findings in these areas indicate the medication is effective. 

In premenopausal women the ovary is the richest source of aromatase and hence estrogen. Aromatase is confined to the granulosa cells and is produced under the influence of gonadotropins (FSH and LH). Despite being a rich source of aromatase, three separate studies have shown that aromatase inhibitors are unable to sufficiently suppress ovarian estrogen production to postmenopausal levels. One explanation for this phenomenon may be a compensatory rise in gonadotrophins which maintains adequate estrogen production, despite the presence of the inhibitor. As such aromatase inhibitors cannot be used in premenopausal breast cancer patients. After menopause, ovarian... 

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... 

Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer Status report 2004. J Clin Oncol 2005 23 619-629. 

Tamoxifen is an oestrogen-receptor antagonist effective in premenopausal, perimenopausal and postmenopausal women with early breast cancer. Aromatase inhibitors, such as anastrazole, may be used only in postmenopausal women. Tamoxifen is administered as tablets. Treatment with tamoxifen is usually given for at least 5 years. 

Dowsett M, Pfister C, Johnston SR, Miles DW, Houston SJ, Verbeek JA, Gundacker H, Sioufi A, Smith IE. Impact of tamoxifen on the pharmacokinetics and endocrine effects of the aromatase inhibitor letrozole in postmenopausal women with breast cancer. Clin Cancer Res 1999 5(9) 2338-43. 

Tamoxifen versus aromatase inhibitors While tamoxifen is still widely regarded as the standard adjuvant endocrine treatment for postmenopausal women with localized breast cancer, provided it is hormone receptor positive, there are problems with recurrence and adverse effects. Reservations have recently been expressed about the future place of tamoxifen, and the case has been made that it is time to move from tamoxifen to the oral aromatase inhibitors (19). 

The roles of tamoxifen and the aromatase inhibitors as adjuvant therapy for early breast cancer in postmenopausal women have been reviewed, distinguishing three approaches replacement of tamoxifen as adjuvant therapy for 5 years (early adjuvant therapy) sequencing of tamoxifen before or after an aromatase inhibitor during the first 5 years (early sequential adjuvant therapy) or the use of an aromatase inhibitor after 5 years of tamoxifen (extended adjuvant therapy) (21). Briefly, the conclusions were that at the time of the survey there was little to choose between the three methods in terms of the balance of benefit and harm. However, like others, the authors stressed that agents of this type are proving to be superior to tamoxifen in preventing recurrence of the disease. 

There may well be a role for combined therapy with both tamoxifen and an aromatase inhibitor if an optimal benefit to harm balance is to be attained, as suggested by a study of a combination of tamoxifen and exemestane for 8 weeks in 33 postmenopausal women with breast cancer (22). There was a striking absence of endocrine adverse effects. 

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. 

Mouridsen HT, Robert NJ. The role of aromatase inhibitors as adjuvant therapy for early breast cancer in postmenopausal women. Eur J Cancer 2005 41 1678-89. 

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. 

Over the past decade, new information has been published regarding the use of a new generation of aromatase inhibitors. These data have changed the way we treat metastatic breast cancer, as well as early-stage breast cancer (as was noted previously). In postmenopausal and castrated women, the main source of estrogen is derived from the peripheral conversion of androstenedione, produced by the adrenal gland, into estrone and estradiol. This conversion requires... 

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