Drug Treatments to Prevent Breast Cancer
Abstract & Commentary
Synopsis: Only tamoxifen has enough evidence to recommend it for the prevention of breast cancer, and its use is limited to very high-risk women with a low risk of side effects.
Source: Cuzick J, et al. Lancet. 2003;361:296-300.
Epidemiologists from England, Italy, and Australia reviewed the combined results of breast cancer prevention trials and added updated results (see Table below). Reports are now available on 4 trials using tamoxifen, 20 mg daily for 5 years, for prophylaxis against breast cancer. In addition, data are available on the effect of raloxifene, derived from the trial investigating raloxifene prophylaxis against fractures in women with osteoporosis.
The combined data indicated a 48% reduction in estrogen receptor-positive cancers and no effect on the incidence of estrogen receptor-negative cancers. The overall relative risk of endometrial cancer with tamoxifen was increased to 2.4, and the relative risk of venous thromboembolic events was 1.9. The length of follow-up and patient numbers do not allow data regarding breast cancer mortality. Cuzick and colleagues estimated the effect of 5 years of tamoxifen treatment, given appropriate survival rates, and concluded that 1000 high-risk women would demonstrate an 18% reduction in mortality within 10 years of diagnosis.
Comment by Leon Speroff, MD
Cuzick et al concluded that the evidence supports tamoxifen reduction of the risk for estrogen receptor-positive breast cancer. But at the same time, they believe that tamoxifen should not be recommended as a preventive agent, except for women at very high risk. This conclusion is based upon the degree of reduction in risk compared with the incidence of side effects. The data are too limited to support the use of raloxifene as prophylactic treatment, and a stronger position awaits the outcome of the STAR trial comparing tamoxifen with raloxifene. The Medical Research Council of the United Kingdom and the National Cancer Institute of the United States have reached similar conclusions.
The evaluation by the National Cancer Institute is very helpful.1 This report is the result of a workshop directed to the development of a program to select the best candidates for tamoxifen treatment. Because the risks associated with tamoxifen (endometrial cancer, stroke, pulmonary embolism, and deep vein thromboembolism) increase with age, balancing the risks and benefits indicates that tamoxifen is best for younger women with an elevated risk of breast cancer (an increased relative risk of approximately 1.7). A similar conclusion was reached by a working group of the American Society of Clinical Oncology.2 This means that only a relatively small number of women will qualify because 85% of women who develop breast cancer do not have an identifiable risk factor.
I am still concerned that the favorable conclusion regarding tamoxifen for prevention is influenced by the American results. The other 3 trials did not achieve statistical significance, results that are usually dismissed on the basis of trial size—the American trial accounted for 47% of the treated women. The recent international trial results achieved statistical significance only when ductal carcinoma in situ cases were included.3 Nevertheless, experts and organizations in the breast cancer world have agreed that tamoxifen reduces the incidence of estrogen receptor-positive cancers in high-risk women.
Women being treated with tamoxifen for prevention of breast cancer should receive appropriate antithrombotic measures, especially during and after major surgery, and during immobility. I disagree with the National Cancer Institute’s position regarding monitoring for endometrial changes, which is to simply refer the patient to a gynecologist for evaluation when the patient bleeds. Endometrial cancer is not the only side effect of tamoxifen. Women on tamoxifen treatment should be examined every 6 months to detect the emergence of endometriosis, ovarian cysts, and uterine enlargement. I believe annual measurement of endometrial thickness by transvaginal ultrasonography is indicated, recognizing that interpretation is difficult and often requires saline instillation (sonohysterography) in order to make accurate measurements. The use of the levonorgestrel-releasing IUD is highly recommended as prophylactic treatment. Interestingly, at the San Antonio Breast Cancer Symposium in December 2002, a study was presented finding no effect of postmenopausal hormone therapy against tamoxifen-induced hot flushing, when the two treatments were administered concomitantly. Hot flushing on tamoxifen is best treated with a serotonin uptake inhibitor.
Important questions remain unanswered. Will long-term follow-up reveal an incidence of tamoxifen-resistant cancers, cancers that are actually stimulated by tamoxifen? Will the incidence of estrogen receptor-negative cancers increase over time? What is the effect of tamoxifen treatment on quality of life and cognition (including the risk of Alzheimer’s disease)?
Dr. Speroff is Professor of Obstetrics and Gynecology at Oregon Health Sciences University in Portland.
1. Gail MH. J Natl Cancer Inst. 1999;91:1829-1846.
2. Chlebowski RT. J Clin Oncol. 1999;17:1939-1955.
3. IBIS Investigators. Lancet. 2002;360:817-824.