Raloxifene and tamoxifen are both effective in reducing the risk of invasive breast cancer, but each has potential disease and quality of life side effects that women and their physicians will need to consider, according to two reports and an editorial published online June 5 by JAMA. The papers are being published online to coincide with the scientific presentation of this information at the annual American Society of Clinical Oncology meeting in Atlanta. The papers will be published in the June 21 issue of JAMA.

Tamoxifen is a selective estrogen receptor modulator (SERM) that has been used to treat both early and advanced breast cancer for more than three decades, according to background information in the article. Raloxifene is a second-generation SERM currently used as a medication for the prevention and treatment of osteoporosis. But clinical trials have shown it may have a role in reducing the risk of invasive breast cancer in postmenopausal women.

Victor G. Vogel, M.D., M.H.S., from Magee-Womens Hospital, University of Pittsburgh School of Medicine, and colleagues from The National Surgical Adjuvant Breast and Bowel Project (NSABP), conducted a randomized clinical trial (Study of Tamoxifen and Raloxifene or STAR trial) at nearly 200 clinical centers throughout North America. Patients were 19,747 postmenopausal women with an average age of 58.5 years with an increased five-year breast cancer risk. The study patients were randomized to receive oral tamoxifen (20 mg/day) or raloxifene (60 mg/day) over five years.

“There were 163 cases of invasive breast cancer in women assigned to tamoxifen and 168 in those assigned to raloxifene (incidence, 4.30 per 1,000 vs. 4.41 per 1,000),” according to the study authors. There were fewer cases of noninvasive breast cancer in the tamoxifen group (57 cases) than in the raloxifene group (80 cases), while there were 36 cases of uterine cancer with tamoxifen and 23 with raloxifene; however, neither of these differences were statistically significant. No differences were found for other invasive cancer sites, for ischemic heart disease events, or for stroke. Thromboembolic events (such as blood clots in the lung or deep veins) occurred less often in the raloxifene group and there were fewer cataracts and cataracts surgeries in that group. The number of osteoporotic fractures in the two groups was similar. There were no differences in the total number of deaths or in causes of death.

The authors suggest that primary care physicians, who are the most involved in preventive care, have not prescribed tamoxifen because it is viewed as a toxic cancer drug. “In contrast, raloxifene is well known to the primary care community and is widely prescribed for the prevention and treatment of osteoporosis in postmenopausal women. More than 500,000 women in the United States are currently taking raloxifene, the majority of whom are older and at lower risk of breast cancer than are the women in the STAR trial.”

In conclusion, the researchers write: “This trial confirms the previously reported benefit of raloxifene in reducing the risk of invasive breast cancer and indicates that raloxifene is as active as tamoxifen in this regard. If raloxifene is approved by the Food and Drug Administration for the prevention of breast cancer, primary care physicians may be more willing, given their experience with raloxifene, to prescribe it for breast cancer chemoprevention than they have been to prescribe tamoxifen.”
(JAMA. 2006;295:doi:10.1001/JAMA.295.23.joc60074. Available to the media pre-embargo at http://www.jamamedia.org.)

Editor’s Note: Please see JAMA paper for authors’ financial disclosures. The study was supported by Public Health Service grants from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, and by AstraZeneca Pharmaceuticals and Eli Lilly and Co.

Patient-Reported Symptoms and Quality of Life
In a related paper, Stephanie R. Land, Ph.D., from the University of Pittsburgh and colleagues from the NSABP STAR trial compared differences in patient-reported outcomes - focused on quality of life, and symptoms in the STAR participants. The patient-reported outcomes were evaluated with standardized surveys.

“No significant differences existed between the tamoxifen and raloxifene groups in patient-reported outcomes for physical health, mental health, and depression, although the tamoxifen group reported better sexual function,” the authors found. “Although mean (average) symptom severity was low among these postmenopausal women, those in the tamoxifen group reported more gynecological problems, vasomotor symptoms, leg cramps, and bladder control problems, whereas women in the raloxifene group reported more musculoskeletal problems, dyspareunia (pain during sexual intercourse), and weight gain.”

“The NSABP’s STAR trial, with its large-scale symptom evaluation and well-powered quality of life substudy, provides a comprehensive, detailed view of the patient experience using raloxifene and tamoxifen. Both of these agents are indicated for prevention in large populations, so these results can be widely used as tools in decision making or in helping a woman anticipate and cope with the sequelae of her chosen agent,” the authors conclude.
(JAMA.2006;295:doi:10.1001/jama.295.23.joc60075). Available pre-embargo to the media at http://www.jamamedia.org.)

Editor’s Note: Please see JAMA study for authors’ financial disclosures. Please see editor’s note above for study funding information.

Editorial: Is Raloxifene the Rising STAR?
“This year, more than 200,000 women in the United States will be diagnosed as having invasive breast cancer,” William J. Gradishar, M.D., from the Northwestern University Feinberg School of Medicine, and David Cella, Ph.D., from the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, write in an accompanying editorial. “The past 20 years of research translating an understanding of basic biology into therapeutics has led to major improvements in the survival and quality of life of patients who carry a diagnosis of breast cancer.”

“The results of the STAR trial offer a pragmatic stepping stone to the next prevention trial in breast cancer. Raloxifene, if not superior to tamoxifen, may be more acceptable to clinicians presenting the option of a preventive drug.”

“The breast cancer chemoprevention sky now includes 2 shining STARs -  tamoxifen and raloxifene. Although neither is a supernova, their benefits include prevention of breast cancer in postmenopausal women at increased risk and, in the case of raloxifene, reduction of fractures related to osteoporosis. Perhaps because the clear benefits are limited to these end points, the relatively modest adverse event profiles and minimally impaired quality of life experienced by these women still may not be enough to convince primary care physicians to be more aggressive than they have been to date in breast cancer chemoprevention.”

American Medical Association (AMA)