A new study has found a possible mechanism for tamoxifen resistance in breast cancer and provides evidence that another cancer drug--gefitinib (Iressa)--may be able to restore tamoxifen's anticancer activity. The study appears in the June 16 issue of the Journal of the National Cancer Institute.
Although adjuvant tamoxifen can reduce the risk of death for women with invasive breast cancer by about 15% over 10 to 15 years, many women do not receive any benefit from the drug. Even among patients most likely to benefit from tamoxifen--those with tumors that express the drug's target, the estrogen receptor (ER)--only 40% to 50% actually benefit. Studies have shown that patients with ER-positive tumors that express high levels of HER2/neu and the ER coactivator AIB1 often develop tamoxifen resistance, but the mechanism of the resistance has not been identified.
To find this mechanism, Rachel Schiff, Ph.D. and C. Kent Osborne, M.D., of the Baylor College of Medicine in Houston, and colleagues studied molecular interactions in breast cancer cells that expressed high levels of both HER2 and AIB1. They found that, in these cells, tamoxifen acted like an estrogen agonist and stimulated tumor growth. However, when the breast cancer cells were treated with the receptor tyrosine kinase inhibitor gefitinib, tamoxifen once again acted as an estrogen antagonist and tumor growth was blocked.
"Our data imply that monotherapy with growth factor pathway inhibitors like gefitinib may have little or only modest benefits on ER-positive, HER2-overexpressing breast cancer, but the results do provide a strong rationale for combining tamoxifen with gefitinib or other EGFR/HER2 pathway inhibitors to overcome … resistance in such tumors. Clinical trials of this new strategy are under way," the authors write.
In an editorial, Daniel F. Hayes, M.D., of the University of Michigan Health System in Ann Arbor, reviews tamoxifen's potential for both harm and good in breast cancer patients. "It is imperative that we now take advantage of the advances in understanding of the biology of these … systems to efficiently select optimal treatment and even further reduce mortality of patients with breast cancer," he writes, adding that "[t]hese steps can only be taken by conducting well-designed clinical trials."