Tamoxifen Adjuvant Therapy for Breast Cancer: Is Forever Too Long?

Source: Fisher B, et al. J Natl Cancer Inst 1996; 88:1529-1542; Swedish Breast Cancer Cooperative Group. J Natl Cancer Inst 1996;88:1543-1549.

Tamoxifen is an effective adjuvant therapy for women with estrogen-receptor positive breast cancer whether the axillary lymph nodes are involved or not. In addition to its positive effects on breast cancer recurrence, tamoxifen has beneficial effects on the cardiovascular system and on bone mineral density. These salutary effects have led many, including myself, to recommend that eligible women should take 20 mg of tamoxifen every day for the rest of their lives. However, tamoxifen is associated with the development of endometrial cancer in about two patients for every 1000 women taking it each year. The question that remains to be answered is whether there is a time point at which the adverse effects of tamoxifen outweigh its benefits.

Two large cooperative group clinical trials have now been reported that offer some data on this question without resolving it definitively. The Swedish Breast Cancer Cooperative Group randomized 3887 postmenopausal women with either positive or negative lymph nodes to two years vs. five years of adjuvant tamoxifen therapy. Patients receiving five years of tamoxifen had a statistically significant improvement in event-free and overall survival compared to patients receiving two years of tamoxifen (10-year survival 80% for 5 years vs 74% for 2 years). The benefit was restricted to women with estrogen receptor-positive tumors but was noted in both node-negative and node-positive women.

NSABP-14 was begun in 1982. It randomized women with estrogen receptor-positive, node-negative breast cancer to receive five years of tamoxifen (1404 women) or placebo (1414 women) in a double-blind fashion. At five years, patients who had received tamoxifen and remained disease-free were randomized a second time to either discontinue tamoxifen (321 women) or continue it for another five years (322 women). Through 10 years of follow-up, patients receiving tamoxifen had a significantly better disease-free survival (69% vs 57%) and overall survival (80% vs 76%) than those receiving placebo. Tamoxifen was associated with a 37% reduction in risk of contralateral breast cancer. For the extended use of tamoxifen, through the first four years of reassignment, disease-free and overall survival were higher for those who discontinued tamoxifen at five years (disease-free survival 92% vs 86%; overall survival 96% vs 94%). Women continuing on tamoxifen had a higher incidence of thromboembolic events (1.75 vs 0.4%) and more endometrial cancers. The authors conclude that therapy with tamoxifen for 10 years is not superior to five years of therapy.

Comment by Dan L. Longo, MD

The optimal duration of tamoxifen therapy in women with estrogen receptor-positive breast cancer is not yet clear, but the data are pretty strong that five years is better than one or two. In addition to the Swedish study noted above, the Eastern Cooperative Oncology Group examined five years vs. one year in both premenopausal and postmenopausal women and found that those receiving five years of therapy had a superior time to relapse, though no survival benefit was detected.1,2However, there are now two studies, NSABP-14 and a Scottish trial,3that not only fail to show any benefit to extending the treatment beyond five years, but hint that there may be some adverse effects. In the Scottish trial, the hazard ratio for adverse events (relapse or death without relapse) was 1.27 for those continuing on tamoxifen, an increased risk that was not statistically significant.

What bad things happen to women on long-term tamoxifen? Unfortunately, not enough women have taken tamoxifen for a long enough time period to define the problems. There is an increased risk of endometrial cancer, the magnitude of which is defined (2 cases per thousand women per year); but endometrial cancer should only rarely be a threat to life. In experimental systems of chronic tamoxifen administration, tamoxifen-dependent tumor growth was observed.4 None of the women developing late breast cancer relapses have yet been documented to have a tumor response to tamoxifen withdrawal.

Unaccounted for in these trials are the positive effects of tamoxifen on the cardiovascular system and the musculoskeletal system. Recent data has even suggested a possible role of estrogen in the prevention of cognitive dysfunction in Alzheimer’s disease, which raises the interesting question of whether tamoxifen exerts any estrogen-like effect on the brain. From the available data, it seems prudent to recommend that women with estrogen receptor-positive, node-negative breast cancer receive tamoxifen for only five years, recognizing that the data are not yet conclusive and the hints of adverse impact are based on very few observations. On the other hand, there are no convincing data one way or the other for estrogen receptor-positive, node-positive breast cancer. Their risk of relapse and death is higher than that of node-negative women. It seems to me that the potential benefits of long-term tamoxifen administration, in terms of its antineoplastic effects and its positive effects on the heart and bones, may be worth the risks in this group. I have not yet seen data that convince me to change my pattern of tamoxifen use in the higher-risk group.

References

1. Falkson HC, et al. J Clin Oncol 1990;8:599-607.

2. Tormey DC, et al. J Clin Oncol 1992;10:1848-1856.

3. Stewart HJ, et al. Br J Cancer 1996;74:297-299.

4. Gottardis MM, Jordan VC. J Steroid Biochem 1988; 30:411-314