Breast cancer in postmenopausal women

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. 

Toremifene is an estrogen receptor antagonist. The pharmacokinetics of toremifene are best described by a two-compartment model, with an a half-life of 4 hours and an elimination half-life of 5 days. Peak plasma concentrations are achieved approximately 3 hours after an oral dose. Toremifene is metabolized extensively, with metabolites found primarily in the feces. Toremifene is used for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor-positive or unknown tumors. Toremifene causes hot flashes, vaginal bleeding, thromboembolism, and visual acuity changes. 

Howell A, Robertson JFR, Abram P, Lichinitser MR, Elledge R, Bajetta E, Watanabe T, Morris C, Webster A, Dimery I, et al. (2004a) Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy a multinational, double-blind, randomized trial. J Clin Oncol 22 1605-1613... 

Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, Norton L, Nickelsen T, Bjarnason NH, Morrow M, Lippman ME, Black D, Glusman JE, Costa A, Jordan VC (1999) The effect of raloxifene on risk of breast cancer in postmenopausal women results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. J Am Med Assoc 281 2189-2197... 

Johnell O, Cauley JA, Kulkarni PM, Wong M, Stock JL (2004) Raloxifene reduces risk of vertebral fractures and breast cancer in postmenopausal women regardless of prior hormone therapy. J Fam Pract 53 789-796... 

Toremifen is a SERM considered a tamoxifen analog characterized by one chlorine atom and is approved for first-line treatment of metastasic breast cancer in postmenopausal women who have tumors that are either ER(+) or of unknown status. In a 3-year face-to-face study with tamoxifen, there were no significant differences between both drugs. The number and profile of adverse events are also similar. Experience with toremifen is limited and far from that accumulated with tamoxifen. 

Martino S, Powles T, Cauley JA et al. (2004b) Effect of raloxifene on incidence of invasive breast cancer in postmenopausal women stratified by baseline serum estradiol results of the Continuing Outcomes Relevant to Evista (CORE) trial. San Antonio Breast Cancer Symposium... 

Toniolo PG, LevitzM, Zeleniuch-Jacquotte N (1995) A prospective study of endogenous estrogens and breast cancer in postmenopausal women. J Natl Cancer Inst 87 190-197... 

Besides contraception, the uses of estrogens can largely be put into three main groups the management of the menopausal and postmenopausal syndrome (its widest use) physiological replacement therapy in deficiency states and the treatment of prostatic cancer and of breast cancer in postmenopausal women. 

Tamoxifen is an oestrogen-receptor antagonist indicated as adjuvant hormonal treatment in oestrogen-receptor-positive breast cancer in postmenopausal women. Common side-effects include alopecia and uterine fibroids. 

Exemestane is known uniquely as an aromatase inactivator. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme causing its irreversable inactivation. Exemestane is used for the treatment of hormonally-responsive breast cancer in postmenopausal women. It is generally well tolerated and adverse events are usually mild to moderate. Adverse events include hot flushes, nausea, fatigue and increased appetite. 

Testolactone is a synthetic drug related to testosterone. It is used for palliative treatment of advanced breast cancer in postmenopausal women and in women who have had their ovaries removed. The principal action of testolactone is reported to be inhibition of steroid aromatase activity and the reduction in estrone synthesis. The most common adverse effects are nausea, vomiting, and anorexia. An advantage is that it does not cause women to develop male characteristics such as a deep voice or facial hair. 

Unlabeled Uses Prevention of fractures, treatment of breast cancer in postmenopausal women... 

It is a competitive partial agonist inhibitor of estradiol at the estrogen receptor and is used mainly in the treatment of advanced breast cancer in postmenopausal women. It is also used in male infertility due to its weaker estrogen effect and lesser side effects. 

Colditz GA, Hankinson SE, Hunter DJ, Willett WC, Manson JE, Stampfer MJ, Hennekens C, Rosner B, Speizer FE. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995 332(24) 1589-93. 

Newcomb PA, Longnecker MP, Storer BE, Mittendorf R, Baron J, Clapp RW, Bogdan G, Willett WC. Long-term hormone replacement therapy and risk of breast cancer in postmenopausal women. Am J Epidemiol 1995 142(8) 788-95. 

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. 

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. 

Nabholtz JM, Buzdar A, Poliak M, Harwin W, Burton G, Mangalik A, Steinberg M, Webster A, von Euler MArimidex Study Group. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women results of a North American multicenter randomized trial. J Clin Oncol 2000 18(22) 3758-67. 

Ross RK, Paganini-Hill A, Krailo MD, Gerkins VR, Henderson BE, Pike MC. Effects of reserpine on prolactin levels and incidence of breast cancer in postmenopausal women. Cancer Res 1984 44(7) 3106-8. 

Come SE, Borges VF. Role of fulvestrant in sequential hormonal therapy for advanced, hormone receptorpositive breast cancer in postmenopausal women. Clin Breast Cancer. 2005 6(suppl 1) S15-S22. 

Androgens Fluoxymesterone Methyltestosterone Testosterone Advanced, inoperable breast cancer in postmenopausal women Masculinization in women [see Chapter 30]... 

Tamoxifen is a competitive partial agonist inhibitor of estradiol at the estrogen receptor and is extensively used in the palliative treatment of advanced breast cancer in postmenopausal women. It is a nonsteroidal agent (see structure below) that is given orally. Peak plasma levels are reached in a few hours. Tamoxifen has an initial half-life of 7-14 hours in the circulation and is predominantly excreted by the liver. It is used in doses of 10-20 mg twice daily. Hot flushes and nausea and vomiting occur in 25% of patients, and many other minor adverse effects are observed. Studies of patients treated with tamoxifen as adjuvant therapy for early breast cancer have shown a 35% decrease in contralateral breast cancer. However, adjuvant therapy extended beyond 5 years in patients with breast cancer has shown no further improvement in outcome. Toremifene is a structurally similar compound with very similar properties, indications, and toxicities. 

The approvals of raloxifene (1) in 1997 and 1999 for the prevention and treatment of postmenopausal osteoporosis ushered a new era of drug development in this field.4 In addition, the effect of raloxifene (1) on breast cancer was a secondary endpoint, and breast cancer risk reduction in postmenopausal women was demonstrated in the large clinical trials MORE, CORE, and RUTH.33-38 These results culminated in the 2007 approval of raloxifene (1) for reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis and for reduction in risk of invasive breast cancer in postmenopausal women at high risk for invasive breast cancer (United States only).21 38 ... 

Aro, A., Mannisto, S., Salminen, I., Ovaskainen, M.L., Kataja, V., Uusitupa, M. 2000. Inverse association between dietary and serum conjugated linoleic acid and risk of breast cancer in postmenopausal women. Nutr. Cancer. 38, 151-157. 

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