Postmenopausal breast cancer treatment

Commercialized for different indications breast cancer treatment, contraception, ovulation induction, prevention and treatment of postmenopausal osteoporosis. 

Fig. 5.7. Effect of daily treatment with 20 mg tamoxifen (solid line), 60 mg toremifene (dotted line), or 200 mg toremifene (dashed line) on mean LH and FSH serum concentrations of postmenopausal breast cancer patients for at least 8 weeks (modified from Ellmen et al. Breast Cancer Res Treat 82 103-111,2003)...

Geisler J, Haarstad H, Gundersen S, Raabe N, Kvinnsland S, Lonning PE (1995b) Influence of treatment with the anti-oestrogen 3-hydroxytamoxifen (droloxifene) on plasma sex hormone levels in postmenopausal breast cancer patients. J Endocrinol 146 359-363... 

Estrogens, estrone (28.1.9), estradiol (28.1.17), ethynylestradiol (28.1.26), diethylstilbe-strol (28.1.33), and chlorotrianisene (30.5.2), are used for palliative treatment of postmenopausal breast cancer, prostate cancer, and breast cancer in men. It is highly probable that the mechanism of action is similar to the mechanism of action of androgens. 

Lonning PE, Taylor PD, Anker G, Iddon J, Wie L, Jorgensen LM, Mella O, Howell A. High-dose estrogen treatment in postmenopausal breast cancer patients heavily exposed to endocrine therapy. Breast Cancer Res Treat 2001 67(2) 111—6. 

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. 

Cohen I, Beyth Y, Azaria R, Flex D, Figer A, Tepper R. Ultrasonographic measurement of endometrial changes following discontinuation of tamoxifen treatment in postmenopausal breast cancer patients. BJOG 2000 107(9) 1083-7. 

Leuprolide acetate, a highly potent synthetic analogue of LHRH, is a nonapeptide (5-oxo-Pro-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-ethylamide acetate) with a molecular weight of -1200 Da. Leuprolide acetate has shown promise for the treatment of infertility, postmenopausal breast cancer, and prostate cancer. Very low oral bioavailability of leuprolide acetate has led to an interest in using the lung as a site for the systemic delivery of leuprolide. Okada et al. [70] have shown that a mixed micellar solution of leuprolide acetate has only 0.05 % oral bioavailability compared to IV leuprolide acetate. This low oral bioavailability may be attributed to poor membrane permeability as well as to significant enzymatic deactivation in the intestine. 

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

Idoxifene has been evaluated as a breast cancer treatment for postmenopausal patients [296, 297]. In one study, 321 postmenopausal patients with unknown receptor status or hormone receptor-positive metastatic breast cancer were randomized to receive either tamoxifen or idoxifene as first-line endocrine therapy for their advanced disease. Complete plus partial response rates were 9 and 13% for tamoxifen and idoxifene, respectively. The median time to progression was slightly higher for idoxifene (140 versus 166 days), but these differences were not statistically significant. Morbidity was similar for both groups. The authors concluded that in postmenopausal women with metastatic breast cancer idoxifene had similar efficacy and toxicity to tamoxifen [298]. However, idoxifene has not been developed further because of concerns about uterine prolapse [299]. This side-effect is not seen with tamoxifen. 

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 ... 

Harris AL, PowlesTJ, Smith IE, CoombesRC, Ford HT, Gazet JC, Harmer CL, Morgan M, White H, Parsons CA, McKinna JA (1983) Aminoglutethi-mide for the treatment of advanced postmenopausal breast cancer. Eur J Cancer Clin Oncol 19 11 17... 

STAR trial (Study of tamoxifen and raloxifene), which was completed in 2006, demonstrated additional utility of raloxifene in the prevention and treatment of breast cancer. In fact, the absence of associated uterotrophic effects with raloxifene suggests that it may be a safer agent than tamoxifen for use as a chemopreventative in high-risk postmenopausal women [3] therefore, raloxifene has very recently become a new option for breast cancer prevention now available for physicians and their patients. 

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. 

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. 

Letrozole is another selective aromatase that inhibits the conversion of androgens to estrogen. Maximum plasma concentrations occur 1 hour after oral dosing concomitant food has not been shown to have an effect on the extent of absorption of letrazole. The terminal half-life is approximately 2 days. Letrozole is used in the treatment of postmenopausal women with hormone-receptor-positive or unknown advanced breast cancer. Side effects include bone pain, hot flushes, back pain, nausea, arthralgia, osteoporosis/bone fractures, and dyspnea. 

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. 

Toremifene is another commercially available SERM for the treatment of breast cancer. It exhibits similar efficacy and tolerability to tamoxifen in the metastatic setting. Cross-resistance to toremifene has been demonstrated in patients with tamoxifen-refractory disease.51 Therefore, toremifene appears to be an alternative to tamoxifen in postmenopausal patients with positive or unknown hormone-receptor status with metastatic breast cancer. 

Fulvestrant is a new agent approved for the second-line therapy of postmenopausal metastatic breast cancer patients who have tumors that are hormone-receptor-positive. Studies examining the role of fulvestrant in the treatment of metastatic breast cancer have compared this agent with anastrozole. Given anas-trozole s mechanism of action, only postmenopausal women were eligible for these trials. There is no biologic reason why fulvestrant should not produce similar outcomes in premenopausal... 

The answer is d. (Hardman, pp 1275-1276J Tamoxifen is an estrogen antagonist used in the treatment of breast cancer. Postmenopausal women with metastases to soft tissue and whose tumors contain an estrogen receptor are more likely to respond to this agent Little benefit is derived from tamoxifen if the tumor does not have estrogen receptors. 

The second group of SERMs includes drugs such as raloxifene (previously named keoxifene), arzoxifene (Fig. 2.2), and LY-117018. Raloxifene was initially designed as a drug to treat breast cancer, but its clinical development was later focused on prevention and treatment of postmenopausal osteoporosis,... 

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