Raloxifene-core

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). 

Siris ES, Harris ST, Eastell R, Zanchetta J, Goemaere S, Diez-Perez A et al (2004) Effect of raloxifene on the risk of nonvertebral fractures after 8 years results from the Continuous Outcomes Relevant to Evista (CORE) study. J Bone Miner Res 19(Suppl 1) F428... 

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). 

It is also important to note that, as happened with tamoxifen, this decrease in risk concentrated exclusively in ER(+) tumors. ER status was determined for 88 cases, and 75% of these were considered positive. The decrease in risk in-ducedby raloxifene administration during the total 8 years of MORE plus CORE reached 76% of the invasive ER(+) cases, compared with the placebo group (0.8 vs. 3.2 cases per 1000 woman-years HR=0.24 95% Cl = 0.15 to 0.40). There was no influence of the raloxifene treatment on the incidence of ER(-) invasive tumors (0.53 versus 0.51 cases per 1000 woman-years HR = 1.06 95% Cl = 0.43 to 2.59). This confirms the hypothesis that raloxifene exerts its protective effect through its binding to breast cell ERs, avoiding the proliferative effect of estrogens to take place. Consequently ER(-) tumors cannot be influenced by the presence of raloxifene in the blood, and no difference in its incidence should be expected between placebo and treated groups (Cauley et al. 2001) (Fig. 10.11). 

Delmas and coworkers (2005) have analyzed the impact of raloxifene treatment on breast cancer incidence over the 8 years of MORE plus CORE depending on the classification of the participants as osteopoenic or osteoporotic. For women assigned to placebo, more cases of invasive and ER(+) invasive breast cancers were reported in the osteopenic than in the osteoporotic group. 

As previously mentioned, HT is considered to increase risk for invasive breast cancer. The ability of raloxifene to reduce breast cancer risk was evaluted after MORE (Lippman 2001 Johnell et al. 2004) and has been evaluated recently with a consideration of all the breast cancer cases diagnosed after MORE + CORE (Purdie et al. 2004). Previous HT use was reported by 2235 women and no previous HT use by 5447 women. In these women, the overall reduction in invasive breast cancer incidence for the 8 years of MORE plus CORE was 66% (HR = 0.34 95% Cl = 0.22-0.50). In the placebo group the incidence of invasive breast cancer was 2.7% in those with prior HT use compared to 2.1% in those with no prior use (p = 0.279). In women with a history of prior HT use, raloxifene significantly reduced invasive breast cancer incidence by 71% (HR = 0.29 95% Cl = 0.14-0.59) compared to placebo. In women with no prior exposure to HT, a 64% reduction in incidence of invasive breast cancer was found in those receiving raloxifeneX (HR = 0.36 95% Cl = 0.22-0.59). The magnitude of risk reduction with raloxifene did not differ irrespective of the previous exposure to HT (interaction p = 0.618). 

Cauley JA, Martino S, Barrett-Connor E et al. (2004) Effect of raloxifene on invasive breast cancer incidence in postmenopausal women stratified by Gail risk assessment results of the Continuing Outcomes Relevant to Evista (CORE) trial. Abstract 1018. American Society of Clinical Oncology... 

Purdie D, Cauley J, Disch D et al. (2004) Effect of raloxifene on incidence of invasive breast cancer in postmenopausal women having a history of prior hormone therapy use results of the CORE trial Abstract. European Society of Medical Oncology (ESMO), Vienna... 

The most commonly observed side effect in patients taking raloxifene or tamoxifen was hot flashes (Agnusdei 1999 Muchmore 2000 Miller 2002). In the study by Mounts et al. (2002) in breast cancer patients < 56 years of age, the most frequent complaints during tamoxifen treatment were hot flashes (85%) and disturbed sleep (55%), whereas in the CORE study (Martino et al. 2004) hot flashes were observed in 12.5% of the raloxifene group vs. 6.9% in the placebo group. 

AF-2 core, in such a way that HI 2 covers the hydrophobic pocket in the LBD, thus precluding the binding of coactivators (Brzozowski et al, 1997 Shiau et al, 1998). Such exciting findings provide an explanation for the mechanism of action of antiestrogens, or at least raloxifene. 

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 ... 

Finally, the RUTH study (Raloxifene Use for the Heart)38 was a placebo-controlled clinical trial following over 10,000 postmenopausal women with coronary heart disease (CHD) or with multiple risk factors for CHD.44 16 This trial demonstrated 44% reduced incidence of invasive breast cancer versus placebo, with 0.6% absolute risk reduction,47 thus confirming the findings from MORE and CORE, while also demonstrating that raloxifene did not increase or decrease risk for coronary events or stroke. However, there was an increase in stroke mortality and incidence of venous thromboembolic events (VTEs) as compared to placebo, already seen in MORE, which resulted in a recommendation that raloxifene should not be used for the prevention or reduction of the risk of cardiovascular disease.21... 

CORE" 5213 postmenopausal women with osteoporosis Raloxifene 60 mg daily or placebo 76% lower risk of estrogen receptor-positive breast cancer after 8 years of raloxifene therapy No new safety concerns were identified during the CORE study. The risk of venous thromboembolism remained increased by about 2-fold. 

WHI, Women s Health Initiative MORE, Multiple Outcomes of Raloxifene Evaluation CORE, Continuing Outcomes Relevant to Evista. 

Although raloxifene is not approved for prevention or treatment of breast cancer, a 4-year trial of raloxifene in women with osteoporosis (not at increased risk for breast cancer) showed a 76% risk reduction for estrogen-receptor-positive breast cancer" (relative risk 0.24, 95% Cl 0.13-0.44). Furthermore, the CORE trial, a study evaluating the efficacy of an additional 4 years of raloxifene therapy in women with osteoporosis, showed that the reduction in estrogen-receptor positive breast cancer incidence continues for up to 8 years" " (hazard ratio 0.24, 95% Cl 0.15-0.40) (see Table 80-9). Raloxifene does not increase breast density. A trial comparing raloxifene with tamoxifen is underway. 

Eli Lilly s raloxifene (Evista) is a selective estrogen receptor modulator (SERM) indicated for osteoporosis and breast cancer. Its core structure is a benzothiophene. 

The synthesis of raloxifene began with the construction of the benzothiophene core structure by acid-promoted cyclization and rearrangement as discussed previously. ... 

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