Tamoxifen is an oral synthetic antiestrogen. It is believed to exert its antiestrogenic activity primarily by competitively blocking the binding of estradiol to the estrogen receptor. When estrogen combines with the estrogen receptor in the cell nucleus, stimulation of cell growth occurs, as well as production of growth factors that function by autocrine and paracrine mechanisms. Breast cancer cells treated with tamoxifen accumulate in the G0/G1 stages of the cell cycle. Tamoxifen is generally considered to be cytostatic rather than cytotoxic, although the significance of this distinction is often overemphasized. Tamoxifen also has nonestrogen receptor-mediated antitumor effects. In the treatment of metastatic disease, tamoxifen has demonstrated substantial activity, particularly in patients with hormone receptor-positive tumors.
Most randomized trials of adjuvant tamoxifen have included some older women. Of the 37,000 women participating in the Oxford overview analysis of tamoxifen, approximately 34% were age 60 or older and approximately 7% were over age 70.
Table 33.8), with benefits increasing with increasing duration of tamoxifen therapy up to 5 years. Based on the overview and randomized trials that have compared 5 years of tamoxifen treatment with a shorter duration, 5 years of treatment has become the standard of care for patients with ER-positive breast cancer. There is also the suggestion that longer duration of therapy is of no additional benefit, although two worldwide trials addressing this issue are ongoing.
The absolute benefits from tamoxifen are dependent on a patient’s risk of recurrence and the proportional reduction in recurrence achievable with tamoxifen (up to 50% with 5 years of therapy). Two randomized trials have examined adjuvant tamoxifen therapy specifically in women 65 years of age or older who had one or more positive axillary nodes. Both trials demonstrated significant improvements in disease-free survival in patients who received tamoxifen, despite competing causes of mortality in this older population. Among women with negative axillary lymph nodes, the benefits of tamoxifen have also been demonstrated, although the absolute risk reduction is generally smaller because the risk of recurrence is lower in such women.
Tamoxifen may have beneficial effects apart from reducing the risk of breast cancer recurrence. Five years of tamoxifen has been shown to reduce the occurrence of contralateral breast cancers by up to 50%, consistent with its preventative effects in women at high risk for breast cancer. The beneficial effects of tamoxifen on breast cancer prevention and risk reduction are thought to be secondary to the antiestrogenic effects of tamoxifen. Other antiestrogenic effects of tamoxifen include vasomotor symptoms and vaginitis.
Because it is a mixed estrogen antagonist and agonist, tamoxifen also has some estrogenic effects. The estrogenic activity is manifested as lowering of serum lipid levels, decreased rate of bone mineral loss, and stimulation of endometrial proliferation. It is not clear whether the effects on the bones and blood lipids can lead to clini-cally relevant improvements in fracture rates or cardiovascular mortality. It is clear that tamoxifen use leads to a significant although small increased risk of endometrial cancer, deep venous thrombosis, and pulmonary embolism. There is also some excess incidence of cataract development among tamoxifen users. Thus, the benefits of tamoxifen must be balanced against the risks for a given individual. Although tamoxifen is generally well tolerated, common side effects include menopausal symptoms, such as hot flashes, and gynecologic symptoms, including vaginal discharge. Importantly, many other symptoms commonly reported by women on tamoxifen, including psychologic symptoms, weight gain, and changes in overall quality of life, have been found to be not significantly different from placebo in large double-blinded studies.
- Biology and Natural History of Breast Cancer in the Elderly
- Prevention of Breast Cancer
- Ductal Carcinoma In Situ (Intraductal Carcinoma)
- Invasive Breast Cancer: Early-Stage Disease
- Alternative Management Strategies for Local Disease
- Adjuvant Systemic Therapy
- Metastatic Breast Cancer
- Quality of Life in Older Women with Breast Cancer
- Patterns of Care
Revision date: July 6, 2011
Last revised: by Andrew G. Epstein, M.D.