Tamoxifen Exemestane

Exemestane is an irreversible aromatase inactivator that binds to the aromatase enzyme to block the production of estrogen from androgens. Exemestane is absorbed rapidly after oral administration, with a terminal half-life of 24 hours. The drug is eliminated primarily by the liver and feces, with less than 1% of the dose excreted unchanged in the urine. Exemestane is indicated for the treatment of advanced breast cancer in postmenopausal women who have had disease progression following tamoxifen therapy. Side effects include hot flashes, fatigue, osteoporosis/bone fractures, and flulike symptoms. 

Options for adjuvant hormonal therapy in postmenopausal women include aromatase inhibitors (e.g. anastrozole, letrozole, or exemestane) either in place of or after tamoxifen. Adverse effects with aromatase inhibitors include hot flashes, myalgia/arthralgia, vaginal dryness/atrophy, mild headaches, and diarrhea. 

Aromatase inhibitors (including anastrozole, letrozole, aminoglutethimide, exemestane, formestane, testolactone), selective estrogen receptor modulators—SERMs (including raloxifene, tamoxifen, toremifene), clomiphene, cyclofenil, fulvestrant Diuretics, amiloride, bumetanide, canrenone, chlorthalidone, etacrynic acid, furosemide, indapamide, metolazone, spironolactone, thiazides, triamterene... 

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 ). 

Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE et al. Survival and safety of exemestane versus tamoxifen after 2-3 years tamoxifen treatment (Intergroup Exemestane Study) a randomised controlled trial. Lancet 2007 369(9561) 559-70. 

Anastrozole, a selective nonsteroidal inhibitor of aromatase (the enzyme required for estrogen synthesis. Figures 40-2 and 40-5), is effective in some women whose breast tumors have become resistant to tamoxifen (see Chapter 54). Letrozole is similar. Exemestane, a steroid molecule, is an irreversible inhibitor of aromatase. Like anastrozole and letrozole, it is approved for use in women with advanced breast cancer (see Chapter 54). 

In 55 overweight or obese postmenopausal women w ho took tamoxifen (n = 27) or exemestane (n = 28) for 1 year, frat mass fell significantly with exemestane but not tamoxifen. Triglycerides and high-density lipoprotein cholesterol fell significantly and low-density lipoprotein cholesterol rose significantly with exemestane (13). 

In 122 postmenopausal patients with metastatic breast cancer who were randomized to exemestane 25 mg/day (n = 62) or tamoxifen 20 mg/day (n = 60), neither exemestane nor tamoxifen had adverse effects at 8, 24 or 48 weeks on concentrations of total cholesterol, HDL cholesterol, apolipoproteins A1 or B, or lipoprotein a (15). Exemestane lowered triglyceride concentrations while tamoxifen increased them. 

In 70 postmenopausal women with completely resected breast cancers who were disease-free after taking tamoxifen for 2—3 years, a switch to exemestane resulted in increases in serum bone alkaline phosphatase and the carboxy-terminal telopeptide of type I collagen and a fall in parathormone bone mineral density worsened (28). 

Carpal tunnel syndrome has been reported in six patients taking aromatase inhibitors (29). Most subsequently experienced relief after withdrawal and/or switching to tamoxifen. In clinical trials of anastrozole and exemestane, carpal tunnel syndrome occurred in about 3% (30,31,32). 

Francini G, Petrioli R, Montagnani A, Cadirni A, Campagna S, Francini E, Gonnelli S. Exemestane after tamoxifen as adjuvant hormonal therapy in postmenopausal women with breast cancer effects on body composition and lipids. Br J Cancer 2006 95(2) 153-8. 

Atalay G, Dirix L, Biganzoli L, Beex L, Nooij M, Cameron D, Lohrisch C, Cufer T, Lobelle JP, Mattiaci MR, Piccart M, Paridaens R. The effect of exemestane on serum lipid profile in postmenopausal women with metastatic breast cancer a companion study to EORTC Trial 10951, Randomized phase II study in first line hormonal treatment for metastatic breast cancer with exemestane or tamoxifen in postmenopausal patients . Ann Oncol 2004 15(2) 211—7. 

Gonnelli S, Cadirni A, Caffarelli C, Petrioli R, Montagnani A, Franci MB, Lucani B, Francini G, Nuti R. Changes in bone turnover and in bone mass in women with breast cancer switched from tamoxifen to exemestane. Bone 2007 40(1) 205-10. 

M, Massimini G, Bliss JM, van de Velde C Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004 350(ll) 1081-92. 

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. 

Love RR, Hutson PR, Havighurst TC, Cleary JF. Endocrine effects of tamoxifen plus exemestane in postmenopausal women with breast cancer. Clin Cancer Res 2005 11 1500-3. 

Exemestane is effective and selective for treating some pustmcnopausal women with hormone-dependent breast cancer, whose disea.se has progressed following tamoxifen treatment. Adverse reactions include a low incidence of... 

Journal of Medicine, was compared with placebo in postmenopausal breast cancer patients who had completed 5 years of tamoxifen therapy. After a median follow-up of 2.4 years, letrozole was associated with superior estimated 4-year DFS compared with placebo in this setting (93% vs. 87% p <0.001). While these results were preliminary, patients were unblinded and allowed to crossover to the active arm of therapy. Therefore effects on survival will never be ascertained. However, further follow-up will be completed with regard to safety and DFS in those patients randomized to letrozole from the beginning of the trial. Based on the results of this study, letrozole received FDA approval in November 2004 for extended adjuvant therapy (i.e., after 5 years of tamoxifen therapy). In another recent trial, patients who had completed 2 to 3 years of adjuvant tamoxifen therapy were randomized to continue tamoxifen or crossover to exemestane for the remainder of the 5 years. After a median followup of 30.6 months, DFS was substantially longer with exemestane compared with continuation of tamoxifen (91.5% vs. 86.8% HR = 0.68,p = 0.00005). Concerns regarding long-term safety also arise with this study, with data indicating a possible increase in cardiovascular disease, osteoporosis, and visual disturbances with exemestane compared with tamoxifen. 

Fallowfield, L.J., Midriewicz, E., Andersen, J., Lonning, P.E., Cocconi, G., Stewart, A., Stuart, N., Snowdon, C.F., Carpentieri, M., Massimini, G. and Bliss, J.M. (2004) The Intergroup Exemestane Study, a randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. The New England Journal of Medicine, 350, 1081-1092. 

Exemestane is an aromatase inhibitor (AI), which causes an irreversible, steroidal aromatase inactivation. It lowers circulating estrogen concentrations in postmenopausal women. Exemestane is 90% bound to plasma proteins. It is extensively metabolized. Exemestane is indicated in advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. Unlabeled uses are for prevention of prostate cancer. 

Exemestane has been tested in a randomized cliifical trial in postmenopausal women with esirogen-receptor-positive breast cancer. Women who had completed 2 to 3 years of adjuvant tamoxifen were randomized to complete a total of 5 years of adjuvant treatment with tamoxifen or exemestane. The unadjusted hazard ratio in the exemestane group versus the tamoxifen group was 0.68, representing a 32% reduction in risk and corresponding to an absolute benefit in terms of disease-free survival of 4.7% at 3 years after randomization. Overall survival was not significantly different in the two groups. 

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