HER2 signaling inhibition increases the antitumor effects of paclitaxel increasing survival in patients with metastatic breast cancer (MBC). EGFR blockade enhances the antitumor activity of HER2 inhibition. EGFR is expressed in 48% of MBC, its expression like HER2, correlating with poor prognosis. HER2 overexpression increases EGFR signaling, and transgenic mice overexpressing HER2 in mammary tissue develop mammary tumors with increased EGFR signaling. OSI-774 is an oral quinazoline inhibitor of EGFR tyrosine kinase and downstream signaling that also inhibits HER2 signaling through receptor heterodimerization. HYPOTHESIS: ErbB 1 blockade by OSI-774 potentiates the antitumor activity of trastuzumab and paclitaxel induces increased apoptosis, differentiation, and inhibition of proliferation and angiogenesis in MBC. SPECIFIC AIMS: 1. To characterize, in a phase I study, the safety of continuous oral OSI-774 and a weekly regimen of trastuzumab and paclitaxel and to recommend a dose for subsequent studies. 2. To determine the importance of EGFR signaling in HER2+ and HER2- disease and to assess in phase II studies whether the anticancer activity of this regimen in HER2+ EGFR+ MBC warrants evaluation in phase III studies. 3. To explore the biologic effects of concomitant EGFR and HER2 blockade in MBC amenable to serial tumor biopsies. STUDY DESIGN: This investigator-initiated, NCI-CTEP sponsored, phase I study will evaluate the safety, dose-limiting toxicities, and maximum tolerated dose of weekly paclitaxel and trastuzumab with oral once daily OSI-774. A non-randomized phase II study will then be performed in two separate cohorts of patients with HER2 and EGFR expressing MBC. Patients untreated in the metastatic setting will be treated using a single stage accrual design. Patients with taxane and trastuzumab refractory disease will be treated utilizing a two-stage design to determine whether EGFR blockade can alter resistance to treatment. Corroborative biological studies will be pursued in 30 patients treated on these studies, who have disease safely amenable to serial biopsy. The agents will be introduced sequentially in the first course of treatment only, trastuzumab being commenced on day 1, oral OSI-774 on day 15, and weekly paclitaxel on day 29. Serial tumor biopsies will be obtained on days 0, 14 and 28 in course 1 to evaluate the effects of HER2 blockade on EGFR expression and signaling, and of combined HER2 and EGFR blockade on tumor proliferation, apoptosis, differentiation (hormone receptor expression) and angiogenesis. RELEVANCE: If these results are favorable, a phase III study of trastuzumab and paclitaxel with or without OSI-774 in patients with MBC is planned.