Background: Integrated analysis of whole genome RNAi screening with computationally reverse engineered interactome models identified IL6/JAK/STAT as a master regulator pathway essential for growth of ErbB2/HER2 positive breast cancer. Ruxolitinib (R), FDA-approved treatment for myelofibrosis, inhibits JAK1 and JAK2. The combination of R plus Trastuzumab (T) is synergistic in tumor growth inhibition in mouse xenografts of HER2 amplified breast cancer cell lines. These data provide a strong rationale for studying the efficacy of combination R and T in a clinical trial. Methods: A multi-center, open-label, phase I/II (P1/2) trial of R plus T in HER2+ metastatic breast cancer (MBC) who have progressed on T-based therapy. P1 will be an adaptive design with 10 patients, using the time-to-event continual reassessment method. The recommended P2 dose (RP2D) will be used in a non-randomized, open-label P2 trial with 30 evaluable patients. Given the anticipated limited overlapping toxicities, 33 patients are expected for the P1/2 (range: 33-42 pts). The duration of a treatment cycle will be 21 days. R will be taken orally twice a day continuously. The P1 dosing range will be 10-25 mg BID. T will be administered on Day 1 of each cycle at standard dosing. The primary endpoint is progression-free survival (PFS). Assuming a historical PFS of 8 weeks with single-agent agent HER2-targeted therapy in HER2+ MBC after progressing on T-based therapy, we predict that patients receiving the combination of R plus T will have a PFS of at least 13 weeks. With a 2-sided alpha of 0.05, we have 80% power to detect a difference with 30 pts. Objective Response Rate (ORR) will be assessed by imaging every 9 weeks. Blood samples will be obtained for biomarker analysis pre-treatment, on-treatment on cycle 2 day 1, and then at progression. Pre-treatment biopsies from archival tissue or new biopsy, prior to cycle 2 day 1, and upon progression of disease will be discussed with pts with accessible disease. Predictive markers include tumor pSTAT3 expression(tumor), tumor gene expression, and serum IL-6, IL-8, and C-reactive protein.