The epidermal growth factor and its receptor (EGFR) play important roles in the proliferation, survival and differentiation of breast cancer cells. ZD1839 (Iressa(R)) is an oral drug that selectively inhibits the tyrosine kinase (TK) activity of the EGFR, effectively blocking the activation of the EGFR pathway. In vitro, ZD1839 inhibits the growth of ER negative breast cancer cells as well as the HER2 over-expressing ER positive breast cancer cells. Chronic treatment with TK inhibitors inhibits mammary tumor development in mice that express both the neu protooncogene and the TGFalpha ligand. More recently, animal studies have shown that ZD1839 inhibits the proliferation of human ductal carcinoma in situ (DCIS) implanted in mice. Tamoxifen, an antiestrogen, was approved in 1998 for use in women at high risk of developing breast cancer to decrease the incidence of this disease. However, Tamoxifen does not reduce the incidence of ER negative breast cancer and in fact, may even increase the risk of ER negative contralateral breast cancer. Our hypothesis is that the EGFR pathway plays a role in the growth of ER negative breast tumors and treatment with ZD1839 will inhibit the activation of the EGFR pathway and decrease cell proliferation and or increase apoptosis in patients with DCIS. Our long-term goal is to use the inhibition of the EGFR pathway for the chemoprevention of breast cancer. We propose to investigate ZD1839 in DCIS in humans because DCIS is an early stage of malignancy that expresses EGFR in a high proportion (50-80%). We will identify the optimal biological markers of EGFR inhibition and correlate these changes with biological endpoints such as cell proliferation and cell death. Mass spectrometry analysis of samples before and after treatment will be analyzed for proteins specifically modulated by ZD1839. The data collected here will be instrumental in the design of future large chemoprevention trials testing ZD1839 in high-risk women.
