This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Two thirds of breast cancer tumors express the estrogen receptor and are estrogen dependent for growth. Tamoxifen treatment is very effective in these cases, but resistance soon develops. Iressa is a potent and selective inhibitor of the EGFR tyrosine kinase and EGFR over-expression is associated with many human cancers: but is uncommon in breast. The rationale for its use here is that there appears to be the involvement of the EGFRs in overcoming the inhibition that tamoxifen delivers. The hypothesis is that Iressa, while having a modest direct effect, will block the pathways that lead to tamoxifen resistance and extend the period of usefulness of that drug.This protocol is a multicenter, industry-sponsored but investigator-initiated Phase II randomized, double-blind, stratified trial that compares Nolvadex (Tamoxifen) plus placebo vs. Nolvadex plus ZD1839 (Iressa) in metastatic breast cancer that is estrogen and/or progesterone receptor positive. Two strata will be investigated. In stratum 1 will be individuals who have never had hormonal treatment (tamoxifen or aromatase inhibitors). In stratum 2 will be individuals who have failed a course of tamoxifen or aromatase inhibitors (after a year resistance to tamoxifen appears to disappear). Those relapsing less than a year of adjuvant therapy or progressing while on tamoxifen will be excluded.
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