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SERMS and the chemoprevention of breast cancer

Experts estimate that more than 170,000 women in the United States will be diagnosed with breast cancer this year. At least 40,000 of them will die. Although the causes of breast cancer are unknown, among the possibilities is an increased susceptibility to the effects of estrogen. If this postulate is correct, then an anti-estrogen potentially could be used to prevent this deadly disease.

Tamoxifen
Tamoxifen is a nonsteroidal compound with both anti-estrogenic and estrogenic effects on select tissues, classifying the drug as a selective estrogen-receptor modulator, or SERM. Tamoxifen's ability to retard or arrest the growth of breast cancer tumor cells eventually led to studies of the drug as a breast cancer treatment. The drug subsequently has been evaluated extensively in numerous breast cancer clinical trials. These studies have established that tamoxifen benefits both those with early disease when used as adjuvant therapy and those with advanced disease.

Tamoxifen has been used as a chemo-therapeutic agent for women with advanced stages of breast cancer for the past 25 years. Since 1985, tamoxifen has been used to treat post-menopausal women with advanced or metastatic breast cancer; post-menopausal women with resected node-positive disease; and both pre-menopausal and post-menopausal women with resected node-negative disease. Subsequent follow-up studies demonstrate that tamoxifen is effective in reducing the recurrence risk of breast cancer and prolonging survival in treated patients.

Tamoxifen's possible usefulness in preventing breast cancer was suggested after several observations. First, studies showed that tamoxifen-treated patients had a statistically significant lower incidence of contralateral breast cancer. Second, in vitro and in vivo animal studies revealed that tamoxifen blocked the initiation and progression of tumors and inhibited the growth of cancer cells by several mechanisms.

In 1992, the National Surgical Adjuvant Breast and Bowel Project (NSABP) launched the first breast cancer prevention trial. The goal of this trial was to evaluate whether five years of tamoxifen therapy reduced the incidence of invasive breast cancer in women at increased risk for the disease. The trial involved 13,388 women at high risk for developing breast cancer in the next five years as calculated by the Gail model. Results demonstrated that tamoxifen reduced the risk of invasive breast cancer by 49 percent.

The decreased risk occurred in women of all ages and in those with a history of lobular carcinoma in situ or atypical hyperplasia. In addition, tamoxifen reduced the risk of non-invasive breast cancer by 50 percent. Tamoxifen administration did not alter the average annual rate of ischemic heart disease but did demonstrate a reduction in hip, spine and wrist fractures.

An independent auditor recommended early termination of the trial as a result of such conclusive findings. Any additional information gained by continuing the trial would have been outweighed by the benefits of providing tamoxifen therapy to women in the placebo group and others at increased risk for developing breast cancer.

Tamoxifen was not without significant side effects in this trial, however. The relative risk of developing endometrial cancer in the tamoxifen-treated group was 2.5. Yet the increased risk was seen only in women older than 50. Furthermore, all endometrial cancers that developed in the tamoxifen group were stage I and cured by surgery.

The incidence of endometrial cancer associated with tamoxifen use is only 2.3 per 1,000 women per year. Deep vein thrombosis (DVT) also was more prevalent among women in the tamoxifen-treated group. Again, the excess risk was confined to women older than 50. The relative risk for these women developing a DVT was 1.71.

Two studies from Europe do not support the view that tamoxifen is effective in reducing breast cancer risk. However, these studies differed significantly from the NSABP trial. The patients enrolled in the Italian Tamoxifen Prevention Study were not at increased risk for developing breast cancer, and approximately one-half of them previously underwent oophorectomy. In addition, the dropout rate was high. Only 149 of the 5,408 participants completed five years of treatment. Similarly, the Royal Marsden Hospital study was designed as a pilot study to examine toxicity and compliance, enrolling only 2,471 women. Participants were much younger than those in the NSABP trial, and 26 percent of those in the Royal Marsden trial received concurrent estrogen-replacement therapy. These differences among study populations may explain the disparate trial results.

Raloxifene
Because of tamoxifen's side effects, the NSABP now has turned its attention to other SERMs. The obvious candidate for breast-cancer prevention is raloxifene. At this point, raloxifene is FDA-approved only for the prevention and treatment of osteoporosis. Yet in the Multiple Outcomes of Raloxifene Evaluation (MORE) study, the invasive breast cancer risk was reduced by 76 percent in post-menopausal women with osteoporosis. Raloxifene has not been studied in a population of women at high risk for developing breast cancer.

The NSABP recently launched the Study of Tamoxifen and Raloxifene (STAR) and is enrolling women across the country. The goal is to enroll 22,000 post-menopausal women who are at increased risk for developing the disease. The trial randomizes women to a daily regimen for five years of either 20 milligrams of tamoxifen or a placebo vs. 60 milligrams of raloxifene or a placebo.

This study will determine whether raloxifene is more or less effective than tamoxifen in reducing the incidence of invasive breast cancer in these high-risk women. A secondary goal of the STAR trial is to determine if raloxifene reduces the endometrial cancer rate compared to tamoxifen.

Ellis Fischel currently is recruiting post-menopausal women at high risk for developing breast cancer to participate in this trial. We are pleased to offer Missouri women this opportunity to decrease their breast cancer risk.

References

1. Jordan VC. Chemoprevention of breast cancer: the coming of age of antiestrogens. Advances in Oncology. 1999;15:3-8.

2. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371-1388.

3. Cummings SR, Norton L, Eckert S, et al. Raloxifene reduces the risk of breast cancer and may decrease the risk of endometrial cancer in post-menopausal women: two-year findings from the Multiple Outcomes of Raloxifene Evaluation (MORE) Trial [abstract 3]. Proceedings of the American Society for Clinical Oncologists. 1998;17:2a.