Raloxifene and Breast Cancer Prevention

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The rationale for the use of SERMs, including raloxifene, as breast cancer preventives is based on a strategic hypothesis formulated when SERM action was first recognized in the late 1980s. The evidence to support the use of raloxifene in this paradigm stems from observations made in the laboratory91,96 and the clinic165 along with close monitoring of ongoing osteoporosis placebo-controlled trials. Previous studies have shown that raloxifene inhibits the growth of dimethylbenzanthracene-induced rat mammary carcinoma94 but it prevents mammary cancer by reducing the incidence of N-nitrosomethylurea-induced tumors91'92 if given after the carcinogen but before the appearance of palpable tumors. However, as would be anticipated with a drug that has a short biological half-life, raloxifene is not superior to tamoxifen at equivalent doses.91 Studies have shown that raloxifene, when administered orally, is rapidly absorbed from the gastrointestinal tract and undergoes extensive phase II metabolism in the liver.166 Hence, its absolute availability is around 2%.166 Because of its low availability, a higher dose of raloxifene must be administrated in vivo to obtain an efficacy equivalent to that with tamoxifen,91,167 which has a low binding affinity for the estrogen receptor but accumulates and is subsequently converted to the active metabolite 4-hydroxytamoxifen.134 For this reason, doses above 60 mg raloxifene daily have been tested in clinical trials to prevent osteoporosis. Interestingly, raloxifene, at a high dose of up to 300 mg daily, produced only modest antitumor activity for the treatment of advanced disease.165

Figure 7 Study design for the Continuing Outcomes Relevant to Evista (CORE) trial. CORE is a multicenter, double-blind, placebo-controlled clinical trial. It is a follow-up to the MORE trial and its purpose is to evaluate the long-term efficacy of raloxifene in reducing the incidence of invasive breast cancer in postmenopausal women with osteoporosis who were previously treated with raloxifene for up to 4 years in the MORE trial. All MORE investigation sites were invited to participate in the CORE trial. From those investigators choosing to participate, all women in the MORE trial (n = 7705 participants) were invited to participate in the CORE trial after their completion or discontinuation from the MORE trial, and 4011 of those women chose to participate. Of the 2500 MORE trial participants who chose not to enroll in the CORE trial, 1217 women were still participating in the MORE trial as of January 1, 1999. The remaining 1283 women had completed their participation in the MORE trial before January 1, 1999, and thus did not contribute data for any of the CORE trial analyses. Fifteen CORE enrollees were diagnosed with breast cancer before January 1, 1999, and were excluded from the CORE breast cancer and sensitivity analyses but were included in the safety analyses. Raloxifene (60 mg day -1) was selected as the only active treatment dose for CORE because the 60 and 120 mg day-1 doses of raloxifene had shown similar risk reduction efficacies in the MORE trial. Women who had been randomized to receive placebo in the MORE trial received placebo in the CORE trial. The CORE trial was designed to continue for a maximum of 4 years, hence, the planned total treatment period will be approximately 8 years from the time of randomization in the MORE trial.

Figure 7 Study design for the Continuing Outcomes Relevant to Evista (CORE) trial. CORE is a multicenter, double-blind, placebo-controlled clinical trial. It is a follow-up to the MORE trial and its purpose is to evaluate the long-term efficacy of raloxifene in reducing the incidence of invasive breast cancer in postmenopausal women with osteoporosis who were previously treated with raloxifene for up to 4 years in the MORE trial. All MORE investigation sites were invited to participate in the CORE trial. From those investigators choosing to participate, all women in the MORE trial (n = 7705 participants) were invited to participate in the CORE trial after their completion or discontinuation from the MORE trial, and 4011 of those women chose to participate. Of the 2500 MORE trial participants who chose not to enroll in the CORE trial, 1217 women were still participating in the MORE trial as of January 1, 1999. The remaining 1283 women had completed their participation in the MORE trial before January 1, 1999, and thus did not contribute data for any of the CORE trial analyses. Fifteen CORE enrollees were diagnosed with breast cancer before January 1, 1999, and were excluded from the CORE breast cancer and sensitivity analyses but were included in the safety analyses. Raloxifene (60 mg day -1) was selected as the only active treatment dose for CORE because the 60 and 120 mg day-1 doses of raloxifene had shown similar risk reduction efficacies in the MORE trial. Women who had been randomized to receive placebo in the MORE trial received placebo in the CORE trial. The CORE trial was designed to continue for a maximum of 4 years, hence, the planned total treatment period will be approximately 8 years from the time of randomization in the MORE trial.

Based on the hypothesis that SERMs could reduce the incidence of breast cancer as a beneficial side effect of the prevention of osteoporosis143 and as a safety requirement for FDA approval, the MORE trial was analyzed for changes in breast cancer incidence. As explained above, the MORE trial was an osteoporosis treatment trial conducted in postmenopausal women comparing the efficacy of raloxifene (60 or 120 mg daily) versus placebo, with breast cancer risk reduction as a predefined secondary endpoint. A 3-year follow-up in the MORE trial168 revealed that raloxifene decreased the risk of of invasive breast cancer by 76% and the risk of estrogen receptor-positive breast cancer by 90%, with no significant effect on estrogen receptor-negative invasive breast cancer. A 4-year follow-up of the MORE trial showed that raloxifene reduced the incidence of all breast cancers by 62% (Figure 6b), invasive breast cancer by 72%, and invasive estrogen receptor-positive cancer by 84% in postmenopausal women, with no significant effect on estrogen receptor-negative invasive breast cancer.169

Due to the positive results from the MORE trial, the National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated the STAR trial82 in June 1999. The STAR trial (Figure 8) is a phase III, randomized, double-blind trial that will compare the effect of raloxifene (60 mg orally) with that of tamoxifen (20 mg orally) in reducing the incidence of invasive breast cancer in postmenopausal women at high risk for the disease over a 5-year period. Trial participants will

Figure 8 The design of the STAR trial. The STAR trial is a phase III, double-blinded trial that will assign eligible postmenopausal women to either daily tamoxifen (20 mg orally) or raloxifene (60 mg orally) therapy for 5 years. It is the first head-to-head trial comparing the effect of raloxifene with that of tamoxifen in reducing the incidence of invasive breast cancer in postmenopausal women at risk for the disease. Approximately 19 000 postmenopausal women 35 years of age or older having at least a 1.66% estimated Gail risk of developing breast cancer or a history of lobular carcinoma in situ (LCIS) are being enrolled. The trial is double-blinded, and study participants will be randomized to receive either 20mgday-1 tamoxifen or 60mgday-1 raloxifene for 5 years. The STAR trial's primary aim is to determine whether long-term therapy is effective in preventing the occurrence of invasive breast cancer in high-risk postmenopausal women. The comparison is to be made to the established drug, tamoxifen. The secondary aim is to establish the relative safety profiles of raloxifene and tamoxifen.

Figure 8 The design of the STAR trial. The STAR trial is a phase III, double-blinded trial that will assign eligible postmenopausal women to either daily tamoxifen (20 mg orally) or raloxifene (60 mg orally) therapy for 5 years. It is the first head-to-head trial comparing the effect of raloxifene with that of tamoxifen in reducing the incidence of invasive breast cancer in postmenopausal women at risk for the disease. Approximately 19 000 postmenopausal women 35 years of age or older having at least a 1.66% estimated Gail risk of developing breast cancer or a history of lobular carcinoma in situ (LCIS) are being enrolled. The trial is double-blinded, and study participants will be randomized to receive either 20mgday-1 tamoxifen or 60mgday-1 raloxifene for 5 years. The STAR trial's primary aim is to determine whether long-term therapy is effective in preventing the occurrence of invasive breast cancer in high-risk postmenopausal women. The comparison is to be made to the established drug, tamoxifen. The secondary aim is to establish the relative safety profiles of raloxifene and tamoxifen.

also complete a minimum of 2 additional years of follow-up after therapy is stopped. The primary aim of the STAR trial is to determine whether long-term raloxifene therapy is effective in preventing the occurrence of invasive breast cancer in postmenopausal women who are identified as being at high risk for the disease. It is the first head-to-head trial comparing tamoxifen with raloxifene. The secondary aim is to establish the net effect of raloxifene therapy, by comparison of cardiovascular data, fracture data, and general toxicities with tamoxifen. The results from the STAR trial are anticipated in 2006.

The significant reduction in risk of invasive breast cancer observed in the MORE trial led directly to the design of the CORE study (Figure 7). Results from the CORE trial170 revealed that the incidences of invasive breast cancer and estrogen receptor-positive invasive breast cancer were reduced by 59% (HR, 0.41; 95% CI, 0.24-0.71) and 66% (HR, 0.34; 95% CI, 0.18-0.66), respectively, in the raloxifene group compared with the placebo group. Raloxifene, however, did not significantly (P = 0.86) alter the incidence of estrogen receptor-negative invasive breast cancer. Over the 8 years of both trials, the incidences of invasive breast cancer and estrogen receptor-positive invasive breast cancer were reduced by 66% (HR, 0.34; 95% CI, 0.22-0.50) and 76% (HR, 0.24; 95% CI, 0.15-0.40), respectively, in the raloxifene group compared with the placebo group.170

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