A number of issues remain to be clarified concerning the use of selective estrogen-receptor modulators (SERMs) in the treatment and prevention of breast cancer. These considerations include identification of the ideal agent; the appropriate target population, particularly for chemoprevention with SERMs; the duration of use; the age at which to begin therapy; and a proper risk/benefit calculation.
The prototype SERM, tamoxifen(Drug information on tamoxifen) (Nolvadex), has been a landmark in the history of breast cancer treatment. The ability of this drug to reduce both recurrences and deaths when used in the adjuvant setting are well known, and the demonstration that it could reduce primary breast malignancies was a milestone in 20th-century medical oncology. Tamoxifen, however, is associated with an increased risk of endometrial carcinoma, cataracts, menopausal symptoms, and thrombotic events. Drs. O’Regan and Gradishar did not specifically address the issue of thrombosis, but this concern becomes particularly important after menopause, especially in women aged 60 years and over.
Gail and colleagues have shown that it is possible to calculate the risk vs benefit of tamoxifen use in a way that considers reduction in breast cancer incidence and osteoporotic fractures along with increased risk of thrombotic events, endometrial cancer, and cataracts. Clinicians who are considering prescribing tamoxifen for risk reduction should be cognizant of this strategy. They should also be aware that the calculation of net benefit or risk is conditioned by the weights assigned by either the patient or her clinician to the individual benefits and risks.
Using this strategy, it is relatively easy to show that all premenopausal women with a 5-year risk of invasive breast cancer of 1.66% or greater derive a positive net benefit from the use of tamoxifen for risk reduction. It is also clear that net benefit is more difficult to demonstrate in postmenopausal women, particularly among those with an intact uterus, and especially in light of the rising baseline risks of thromboembolic events associated with increasing age. Nevertheless, women at a moderate to high risk of invasive breast cancer who are older than 50 years still derive net benefit from using tamoxifen for risk reduction. Additional research is needed to identify the best strategy for communicating the relative risks/benefits and a net benefit calculation for the entire at-risk population.
Large Studies of Tamoxifen Risk/Benefit
The largest, and perhaps most informative, review of the association between exposure to tamoxifen and development of endometrial carcinoma appears in the National Surgical Adjuvant Breast and Bowel Project (NSABP) report on study B-14. This evaluation suggests that tamoxifen-associated endometrial carcinomas can occur over prolonged periods after the administration of tamoxifen. Unlike the information cited by Drs. O’Regan and Gradishar, these data suggest that endometrial tumors associated with tamoxifen may not merely occur after short durations of therapy. Importantly, however, the Breast Cancer Prevention Trial showed that endometrial cancer incidence was not increased among menstruating, premenopausal women; the increase in risk was confined only to nonmenstruating, postmenopausal women.