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Journal of the National Cancer Institute

The oral drug ZD1839, also known as gefitinib, prevented the development of estrogen receptor (ER)-negative breast cancer in a mouse model, which raises the possibility that the drug could be a preventive agent for ER-negative breast cancer. The results appear in the December 17 issue of the Journal of the National Cancer Institute.

ER-negative breast cancers are not dependent on estrogen to grow and do not respond to antiestrogen drugs such as tamoxifen and raloxifene.

ZD1839, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, blocks the cellular signaling pathway that contributes to tumor survival and growth, and studies have shown that ZD1839 is effective at inhibiting the growth of various types of cancer cells, including breast cancer cells.

To test whether ZD1839 can inhibit the growth of ER-negative breast cancer cells, Chunhua Lu, M.D., Ph.D., and Powel H. Brown, M.D., Ph.D., of the Baylor College of Medicine in Houston, and their colleagues treated ER-negative normal, immortalized (i.e., precancerous), and cancerous breast cells with ZD1839. They also examined the effect of ZD1839 on the development of ER-negative breast tumors in transgenic mice.

Treatment with ZD1839 suppressed the growth of ER-negative normal, immortalized, and cancerous breast cells. Moreover, ZD1839 treatment of transgenic mice that normally develop breast tumors in approximately 230 days delayed the formation of ER-negative tumors to more than 310 days. ZD1839 also reduced proliferation of normal breast cells by 20.3% and of tumor cells by 42%.

In an accompanying editorial, Dennis J. Slamon, M.D., Ph.D., of the University of California at Los Angeles Jonsson Comprehensive Cancer Center, and his colleagues commend the new findings, but caution that long-term safety data are not available for ZD1839.

They point out that some patients taking ZD1839 for non-small-cell lung cancer have developed interstitial lung disease, a rare but potentially dangerous side effect, particularly if ZD1839 is used as a chemopreventive agent in healthy women.

In addition, they say, the effectiveness of ZD1839 and other EGFR inhibitors may be limited to a subpopulation of patients in whom EGFR is involved in tumor formation or growth.

'Before we develop gefitinib as a chemopreventive agent, further research is needed to find and validate predictive factors that can be used to identify patients and healthy women likely to respond to gefitinib as a therapeutic and chemopreventive agent,' they conclude.

Contact: Kimberlee Barbour, Baylor College of Medicine, 713-798-7971; fax: 713-798-3692, kbarbourbcm.tmc.

Editorial: Kim Irwin, Jonsson Comprehensive Cancer Center, 310-206-2805, kirwinmednet.ucla. Lu C, Speers C, Zhang Y, Xu X, Hill J, Steinbis E, et al. Effect of epidermal growth factor receptor inhibitor on development of estrogen receptor-negative mammary tumors. J Natl Cancer Inst 2003;95:1825-33.

Editorial: Konecny GE, Wilcon CA, Slamon DJ. Is there a role for epidermal growth factor receptor inhibitors in breast cancer prevention. J Natl Cancer Inst 2003;95:1813-15.

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