Raloxifene trial

Estrogen plays a central role in its pathogenesis, and treatment with estrogen deprivation has long been recognized to be an effective therapy. Tamoxifen is the first selective estrogen receptor modulator SERM to be widely used for the treatment of breast cancer and has been demonstrated to reduce the risk of breast cancer in high-risk women. Raloxifene is a second-generation SERM that has estrogenic effects on bone and lipid metabolism, and antiestrogenic effects on breast tissue.

However, combination therapy induced a significantly smaller increase in bone resorption versus teriparatide alone and significantly increased total hip BMD versus baseline.

Introduction: The effects of combining two approved treatments for osteoporosis with different modes of action were examined by comparing teriparatide [rhPTH ] monotherapy with combination teriparatide and raloxifene therapy.

Lumbar spine BMD significantly increased 5. Cumulative incidence at 6 years for tamoxifen and raloxifene was Of these women, in the tamoxifen group and in the raloxifene group had cataract surgery. The RR for cataract surgery was 0. In the STAR trial, the effect of raloxifene on invasive breast cancer was equivalent to that of tamoxifen with more-favorable effects on uterine malignancy and clotting events.

Symptomatic side effects are acceptable. In summary, the available data indicate that raloxifene represents an acceptable alternative to tamoxifen for the reduction of the risk of postmenopausal breast cancer in high-risk women [ 30 ]. Among younger postmenopausal women who are at increased risk of breast cancer, raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer. Previous studies have shown that raloxifene does not increase the risk of uterine malignancy compared with placebo.

In the STAR trial, only 59 invasive uterine cancers were diagnosed in both study groups during more than 76, woman-years of follow-up. The rates of uterine cancer were 1. This difference did not reach statistical significance RR: 0. However, endometrial hyperplasia, a risk factor for endometrial cancer, was far more common in the tamoxifen-treated group than in the raloxifene group and was statistically significant RR: 0.

The number of participants undergoing a hysterectomy for noncancer-related reasons was significantly reduced in the raloxifene group RR: 0. It is important to note that the difference between the treatment groups in noncancer-related hysterectomies has probably caused an underestimate of the true magnitude of endometrial cancer risk associated with tamoxifen and an underestimate of the true magnitude of difference between the two treatment groups for this end point.

Across all placebo-controlled trials with raloxifene, however, in situ cancers occurred more often with raloxifene than with placebo or tamoxifen [ 4 , 15 , 19 , 29 ]. The STAR trial may have been underpowered to detect such a difference. Therefore, the clinical impact of this finding remains to be seen. Similar results were observed, however, in the MORE and CORE studies, in which raloxifene did not reduce the risk of noninvasive breast cancer, although the number of events in those studies was very small.

All of these results taken together suggest that different SERMs have unique and specific mixes of benefits and risks and that neither a benefit nor a risk seen with one SERM can be generalized across the entire class.

Most of the STAR cases were diagnosed as a result of mammograms, demonstrating increasing calcifications. The individuals underwent careful follow-up and, as a result, their cancers were small and most were treated surgically with lumpectomy.

The difference between tamoxifen- and raloxifene-treated individuals with DCIS was quite small 0. The CORE results through 8 years of follow-up show that raloxifene continues to offer a significant reduction in invasive disease, suggesting that raloxifene has a durable benefit despite this lesser impact on noninvasive disease.

Among women in the STAR trial quality-of-life analysis, mean physical, mental and depression component scores worsened modestly over 60 months of observation, with no significant difference between the two groups [ 28 ]. Sexual function was slightly better for participants assigned to tamoxifen age-adjusted repeated measure odds ratio: 1. Of the women in the symptom assessment analyses, those in the raloxifene group reported greater mean symptom severity over 60 months of assessments than those in the tamoxifen group for musculoskeletal problems, dyspareunia and weight gain, but the differences were not clinically meaningful.

Overall, no significant differences existed between the tamoxifen and raloxifene groups in patient-reported outcomes for physical and mental health, and depression, although the tamoxifen group reported better sexual function. In high-risk, younger postmenopausal women, raloxifene appears to offer a net benefit when comparing reduction of the risk of breast cancer and the prevention of fractures with the risk of stroke, venous thromboembolic events, uterine events and symptomatic side effects [ 30 ].

It offers greater net benefit to women with an intact uterus than does tamoxifen. Raloxifene has not been studied in and its use is not appropriate in premenopausal women who are at increased risk of breast cancer; tamoxifen remains the drug of choice for these patients. Chemoprevention of breast cancer in healthy women offers an attractive potential for prevention of this disease. It is essential to identify women who will benefit from these interventions.

Raloxifene has similar risk-reduction activity when compared with tamoxifen but has less toxicity, particularly on the uterus, making it a more attractive option than tamoxifen for use as a breast cancer risk-reduction agent in postmenopausal healthy women. Published clinical trials demonstrate that the greatest clinical benefit with the fewest side effects occur in high-risk, younger postmenopausal women. In this population of women, raloxifene appears to offer a net benefit when comparing reduction of the risk of breast cancer and the prevention of fractures with the risk of stroke, venous thromboembolic events, uterine events and symptomatic side effects.

The potential market for a compound shown to reduce the risk of breast cancer in postmenopausal women who are at increased risk for breast cancer is more than 10 million women in the USA alone [ 11 ]. The development of the selective aromatase inhibitors AIs has had an important impact on the adjuvant treatment of post-menopausal women with receptor-positive breast cancer [ 31 ]. In various adjuvant trials, the AIs have improved disease-free survival and overall survival and have had fewer life-threatening side effects than tamoxifen [ 31 - 33 ].

The results of a European study, the International Breast Cancer Intervention Study 2 trial, will determine whether the AI anastrozole is effective in preventing breast cancer in high-risk postmenopausal women [ 32 , 33 ].

In this study, anastrozole was compared with placebo in healthy high-risk postmenopausal women. The National Cancer Institute of Canada Clinical Trials Group has also begun its MAP-3 study comparing exemestane to placebo in postmenopausal women at increased risk to determine if exemestane reduces the incidence of invasive breast cancer [ 34 ]. Based on all of these considerations, it is likely that an increasing number of postmenopausal women will be screened and identified as being at increased risk of breast cancer.

They will have positive net benefit from using either raloxifene or AIs for breast cancer-risk reduction. The burden of morbidity and mortality from breast cancer will, very probably, decline in the population as both patients and physicians embrace primary risk reduction and employ these drugs [ 35 ].

There are multiple positive considerations for the use of selective estrogen receptor modulators SERMs for breast cancer risk reduction. Extensive experience from prospective investigations has established its safety and efficacy in the management of postmenopausal osteoporosis. Although it has no apparent beneficial effect on coronary heart disease, it has no adverse effect either. Three prospective clinical trials have established its benefit in reducing the risk of invasive breast cancer and it offers safety advantages compared with tamoxifen in postmenopausal women who are at increased risk for breast cancer.

Symptomatic side effects are acceptable as reported in the large, prospectively blinded clinical populations summarized in this article and followed during years of raloxifene administration.

The risk of other cancers, fractures, ischemic heart disease and stroke are similar for both raloxifene and tamoxifen.

Raloxifene offers an alternative to tamoxifen for the reduction of breast cancer risk in high-risk postmenopausal women with a superior risk—benefit profile based upon the benefits and risks reviewed here. Postmenopausal women over 35 years of age with either Gail model risks of breast cancer greater than 1.

When used for reducing the risk of breast cancer, raloxifene should be administered in a dose of 60 mg once daily; alternate doses and schedules have not been evaluated for either safety or efficacy. American Society of Clinical Oncology offers news and meeting reports, technology assessments, education and training, practice resources, and updates on legislative activities for cancer professionals www.

National Cancer Institute of the United States provides information for both health professionals and the public. National Library of Medicine U. National Institutes of Health U. Department of Health and Human Services. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators.

Cognition Aging. Drug: tamoxifen Drug: raloxifene. Phase 3. Study Type :. Interventional Clinical Trial. Actual Enrollment :. Triple Participant, Investigator, Outcomes Assessor. Study Start Date :. Actual Primary Completion Date :. Actual Study Completion Date :. Experimental: Star participants assigned to Tamoxifen Participants in the parent study, STAR assigned to Tamoxifen who were 65 or older at time of enrollment.

Drug: tamoxifen oral tamoxifen plus placebo daily for 5 years Other Name: Nolvadex. Experimental: Star participants assigned to Raloxifene Participants in the parent study, STAR assigned to Raloxifene who were 65 or older at time of enrollment. Drug: raloxifene oral raloxifene plus placebo daily for 5 years Other Name: Evista, Keoxifene. Camp Pendleton, California, United States, Woodland Hills, California, United States, Colorado Springs, Colorado, United States, Washington, District of Columbia, United States, Fayetteville, North Carolina, United States, Greenville, North Carolina, United States, Hendersonville, North Carolina, United States, Charleston, South Carolina, United States,