1014 Background: Hyperactivation of the PI3K pathway has been associated with trastuzumab (T) resistance in breast cancer (BC). Everolimus (E) selectively inhibits the mammalian target of rapamycin (mTOR), which is activated downstream of PI3K. Preclinical studies showed that the combination of E and T can overcome T resistance in human BC xenografts. We conducted a multicenter phase I/II trial to determine the safety and efficacy of E plus T in patients (pts) with T-resistant metastatic breast cancer (MBC). Methods: Eligible pts had history of biopsy- proven HER2-overexpressing BC and radiographic evidence of MBC, progressive disease after T-based therapy for MBC, ≤2 prior T-based regimens and one lapatinib-based regimen for MBC, measurable disease by RECIST, and LVEF ≥50%. Primary objectives were: (1) to identify the optimal dose and pharmacokinetics (PK) of E in combination with T in a phase I trial and (2) to determine the efficacy of E plus T in a phase II trial. In the first phase, we planned to eva...