Background: Increased signaling through growth factor receptor pathways, including HER2, has been demonstrated to play a role in resistance to endocrine therapy. Efficacy of inhibiting HER2 and mTOR in HER2-negative, hormone-resistant breast cancer has been previously demonstrated. We evaluated the ability of inhibition of HER2 with trastuzumab (TRAST) and/or mTOR with everolimus (EVER) to reverse resistance to endocrine therapy in patients with hormone receptor (HR)-positive HER2-negative metastatic breast cancer (MBC). Methods: Eligibility included HR-positive, HER2-negative (IHC 1+ or 2+ and/or FISH negative) MBC on metastatic biopsy and documented progression within 6-months of starting an endocrine agent in the metastatic setting. Patients continued on the endocrine agent they had experienced disease progression on and were randomized to receive TRAST (8mg followed by 6mg every 3-weeks) or EVER 10mg daily. At disease progression the other agent (TRAST or EVER) was added. Biopsies of metastatic lesions were obtained prior to study entry where possible. Results: To date 38 patients have been randomized to TRAST (n = 13) or EVER (n = 22), 3 patients not evaluable. All patients continued the endocrine agent on which they had most recently experienced disease progression. The median PFS is 1.5 (95% CI 1.5 to 4) and 6 (95%CI 4 to 15) months (mos.) for patients initially randomized to TRAST and EVER respectively. At disease progression 13 patients in the TRAST arm received EVER and 5 in the EVER arm received TRAST. The overall PFS for this group is 5.5 (95% CI 3 to 8) mos: 7 (95% CI 3 to 13) mos. for patients in the TRAST arm who then received EVER; and 4 (95% CI 1.5 to 7) mos. for patients in the EVER arm who received TRAST. There were no unexpected toxicities though 2 patients were taken off study for decreases in ejection fraction. Metastatic biopsies are available for 57% of patients. Conclusions: This trial demonstrates the efficacy of inhibiting mTOR alone or in combination with HER2 in patients with hormone-resistant HER2-negative breast cancer, suggesting that inhibition of this growth factor pathway may restore sensitivity to endocrine therapy. Updated results and correlative studies will be presented. Clinical trial information: NCT00912340.