Background: Overexpression of HER2/neu is associated with tamoxifen resistance in breast cancer (Osborne CK et al. J Natl Canc Inst 2003; 95:353-361). However pts may present with both estrogen receptor (ER) and HER2/neu + tumors. The benefit of adding fulvestrant to trastuzumab is unclear. The objective of the study was to determine the effect of trastuzumab on fulvestrant therapy. Methods: This was an IRB approved record review of patients (pts) from three medical oncologists with biopsy-proven ER+ metastatic breast cancer treated with fulvestrant who also had their primary tumor tested for HER2/neu. Demographic data collected included age at diagnosis, type and stage of cancer, original and metastatic ER, progesterone receptor (PR), and HER-2/neu biomarkers, and site(s) of metastasis, and primary local and systemic treatment. All pts with HER-2/neu + primary tumors received trastuzumab. The duration of fulvestrant therapy was calculated. Time to clinical disease progression on fulvestrant was measured as a surrogate for duration of clinical benefit. Results: Eighty-five metastatic ER+ fulvestrant treated breast cancer pts with known primary tumor HER2/neu status were identified and the duration of therapy calculated. All eleven (13%) pts with documented HER2/neu + primary tumors received trastuzumab. The duration of therapy for HER2/neu + pts (772 (51-1911) days (median (range)) was longer than HER2/neu negative pts (360 (60-2,739) days, p=0.059). The median duration of fulvestrant therapy was 425 days. Pts with HER2/neu + tumors were more likely to be treated beyond the median fulvestrant therapy with an odds ratio of 6.2 (1.26 to 30.92 95% confidence interval, p=0.0249). Conclusions: Trastuzumab plus fulvestrant therapy was associated with a more prolonged clinical response than fulvestrant alone in pts with metastatic breast cancer. This synergism may be due to the effect of trastuzumab inhibiting the activation of transcriptional coactivator MED1, a recently discovered key crosstalk point between HER2/neu and ER signaling pathways in mediating endocrine resistance (Cancer Res 2012;72(21):5625;PLoS One 2013; 8:e70641).