Tamoxifen substantially cuts the risk of invasive and noninvasive breast cancer, researchers confirmed in an extended follow-up of the National Surgical Adjuvant Breast and Bowel Project that was initially reported in 1998.
This update of the NSABP study involved 13,207 women at high risk of developing breast cancer who had participated in the initial study in 1992–1997 and were followed for an additional 7 years. A total of 6,597 subjects composed the tamoxifen group and 6,610 formed the placebo group.
All the benefits and risks of tamoxifen therapy that had been reported in the initial study were borne out in this extended study, according to Bernard Fisher, M.D., scientific director of the NSABP and distinguished surgical professor at the University of Pittsburgh.
Tamoxifen was linked to a 43% reduction in the cumulative rate of invasive breast cancer. The rate was 24.8 cancers/1,000 women taking tamoxifen, compared with 42.5/1,000 women taking placebo.
Similarly, tamoxifen reduced the cumulative rate of noninvasive breast cancer by 37%. The rate was 10.2 cancers/1,000 women taking tamoxifen, compared with 15.8/1,000 women taking placebo.
The drug cut the risk of breast cancer in all subgroups of subjects categorized by age, history of lobular carcinoma in situ (LCIS), history of atypical hyperplasia, and level of predicted risk of breast cancer.
Among women who took tamoxifen, the incidence of breast cancer remained relatively constant throughout the 7 years of follow-up, remaining stable for at least 2 years after they finished a 5-year course of the drug (J. Natl. Cancer Inst. 2005; 97:1652–62).
As it did in the initial NSBAP study, tamoxifen also reduced the risk of osteoporotic fractures of the hip, spine, and radius in this extended study. Among women aged 50 and older—the group that sustained nearly 90% of such fractures—tamoxifen decreased the fracture rate by 29%.
However, this extended study also confirmed the adverse effects of the drug that had been reported in the 1998 study regarding endometrial cancer, thromboses, and cataracts.
Tamoxifen increased the rate of invasive endometrial cancer in women aged 50 or older. The cumulative rate was 15.6 such cancers/1,000 women, compared with 4.7/1,000 women in the placebo group. However, two related findings were encouraging. A total of 67 of the 70 cases of invasive endometrial cancer were stage I malignancies, and tamoxifen therapy did not alter the risk for cancer at sites other than the breast and endometrium, the investigators noted.
The drug also raised the rate of pulmonary embolism in women aged 50 or older. Tamoxifen also increased the rates of stroke and deep vein thrombosis, but not to a statistically significant degree.
Women who took tamoxifen also were at slightly higher risk of developing cataracts than were those who received placebo.
“Evaluation of the frequency of other adverse eye-related events from tamoxifen failed to demonstrate vision-threatening toxicity,” the investigators said.
Mortality rates were similar among women who took tamoxifen and those who took placebo. This finding was not unexpected, given that it would require much longer follow-up—most likely 15–20 years—to detect a definitive reduction in mortality, Dr. Fisher and associates noted.
New trials on breast cancer prevention currently are underway in postmenopausal women “to evaluate other agents that could be more effective than tamoxifen in decreasing the risk of breast tumors and reducing the frequency of undesirable side effects noted with the drug. … Until one of these trials demonstrates a greater net benefit from an alternative therapy, tamoxifen remains the only proven chemopreventive treatment for breast cancer risk reduction,” they added.