Breast cancer raloxifene

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. 

In addition to effects on bone, raloxifene may have effects in breast tissue and on the cardiovascular system. A secondary end point of the MORE trial evaluated the effects of raloxifene on the primary prevention of breast cancer and found a significant reduction in all types of breast cancer.33 Raloxifene decreases total and low-density lipoprotein (LDL) cholesterol,34 and studies are evaluating its effect on reducing the risk of cardiovascular disease.35... 

Raloxifene (like tamoxifen) is associated with decreased breast cancer risk. Raloxifene is associated with decreases in total and low-density lipoprotein cholesterol, neutral effects on high-density lipoprotein cholesterol, but slight increases in triglycerides no beneficial cardiovascular effects have yet been demonstrated. 

Tamoxifen is discussed in Chap. 61, Breast Cancer raloxifene is discussed in Chap. 3, Osteoporosis. Raloxifene decreases bone loss in recently menopausal women without affecting the endometrium and has estrogen-like actions on lipid metabolism. It may exacerbate vasomotor symptoms, and it increases the risk of venous thromboembolism and stroke. 

Raloxifene treatment of osteoporosis was associated with a 76% risk reduction for estrogen-receptor positive breast cancer. An additional study showed that this reduced risk continues for up to 8 years. Among women at high risk for breast cancer, raloxifene was as effective as tamoxifen in reducing the risk of invasive breast cancer and had a lower risk of thromboembolic events. 

Tamoxifen and raloxifene reduce the rates of invasive breast cancer in women at high risk for developing the disease. Rates of endometrial cancer and deep vein thromboses are higher in patients receiving tamoxifen but overall quality of life is similar between the two agents. 

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,... 

The rate of invasive ER-positive breast cancer, a secondary objective in the MORE trial, showed an 84% reduction after 4 years of followup (Cauley et al. 2001) moreover, during the subsequent 4 years of followup in the so-called CORE trial (Continuous Outcomes Relevant to Evista), invasive ER-positive breast cancer, the primary objective of the study, was reduced by 66%. Over the 8 years of both trials, the incidences of invasive breast cancer and ER-positive invasive breast cancer were reduced by 66% and 76%, respectively, in the raloxifene group compared with the placebo group (Martino et al. 2004). These effects have not been associated with harmful effects on the endometrium (Cohen et al. 2000) or the pelvic floor (Goldstein et al. 2001). 

Cauley JA, Norton L, Lippman ME, Eckert S, Krueger KA, Purdie DW, et al. (2001) Continued breast cancer risk reduction in postmenopausal women treated with Raloxifene 4-year results from the MORE trial. Breast Cancer Res Treat 65 125-134... 

Dowsett M, Bundred NJ, Decensi A, Sainsbury RC, Lu Y, Hills MJ, et al. (2001) Effect of raloxifene on breast cancer cell Ki67 and apoptosis a double-blind, lacebo-controlled, randomized clinical trial in postmenopausal patients. Can Epidemiol Biomar Prev 10 961-966... 

Gutman M, Couillard S, Roy J, Labrie F, Candas B, Labrie C (2002) Comparison of the effects of EM-652 (SCH570068), tamoxifen, toremifene, droloxifene, idoxifene, GW-5638 and raloxifene on the growth of human ZR-75-1 breast cancer in nude. Int J Cancer 99 273-278... 

Jordan VC, Morrow M (1999) Tamoxifen, raloxifene, and the prevention of breast cancer. Endocr Rev 20 253-78... 

Martino S, Cauley JA, Barrett-Connor E, Powles TJ, Mershon J, Disch D, et al. (2004) Continuing Outcomes Relevant to Evista breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Nad Cancer Inst 96 1751-1761... 

Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Wolmark N (2002) The study of tamoxifen and raloxifene preliminary enrollment data from a randomized breast cancer risk reduction trial. Clin Breast Cancer 3 153-159... 

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... 

Experimental studies showed antitumoral effects of raloxifene in different in vitro preparations and animal models. Raloxifene has been able to inhibit the mitogenic effect induced by estrogens on ZR-75-1 cells, an estrogen responsive human breast cancer cell line (Poulin et al. 1989). In a well-accepted rat model of breast cancer induced by nitroso-methyl urea (NMU) raloxifene significantly suppressed the development of breast tumors and acted synergistically with 9 cis-retinoic acid (Anzano et al. 1996). 

The strongest clinical information on the effects of rakmfen on breast cancer risks emerges from the MORE study. As a reminder, this study included 7705 osteoporotic women randomized either to placebo (2576) or raloxifene (5129), either 60 or 120 mg. Mammographic evaluation was optative during the first year but mandatory at the second, third, and fourth years. At the six-month followup controls the patients were asked about any mammary event, and in the... 

From the first evaluations a positive effect of raloxifene tratment on the incidence of breast cancer was detected (Cummings et al. 1999). During the 4 years of treatment 79 breast cancer cases were detected and 77 of them were confirmed by the review board. In the placebo group 44 cases were identified, of which 39 were invasive, whereas in the raloxifene-treated group 33 cases were detected and 22 were invasive. The differences between both groups appeared progressively and tended to increase over time. This means a relative risk of 0.38 (IC 95% 0.24-0.58) or, in other words, a reduction in the incidence of breast cancer of 68%. 

During the 4 years of the trial 61 cases of breast cancer were reported and confirmed. Of these, 30 were in the placebo group (28 invasive) and 31 were in the raloxifene group (24 invasive). This means a 59% reduction in the incidence of invasive breast cancer in the raloxifene group as compared with women receiving placebo (2.1 vs. 5.2 cases per 1000 woman-years HR = 0.41, Cl = 0.24 to 0.71). Only nine intraductal, noninvasive breast cancers were detected, seven in the raloxifene group and two in the placebo group. The treatment with raloxifene reduced the overall incidence of breast cancer by 50%. The results... 

Considering all 7705 MORE participants from the moment of the initial randomization to the end of their participation in either MORE or CORE, a total number of 121 breast cancers were adjudicated, 56 cancers in the raloxifene group and 65 in the placebo group. Of these 58 in the placebo group (4.2 cases per 100 woman-years) and 40 in the raloxifene group (1.4 cases per 1000 woman-years) were invasive. Consequently, raloxifene induced a 66% reduction in the incidence of invasive breast cancer compared with the placebo group (HR = 0.34,95% Cl = 0.22-0.50) (Martino et al. 2004b) (Fig. 10.10). 

Fig. 10.10. Cumulative incidence of invasive breast cancers during 8 years of treatment either with raloxifene (dotted line) or placebo (solid line) Reproduced with permission from Martino et al. (2004)...

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