Background: IBC is an aggressive form of breast cancer with poor prognosis. Combined multi-modality Rx results in a 5 year OS of 30-50%, underscoring the unmet need for targeted Rx. Our preclinical research in cell lines and xenografts identifies a role for activated PI3K/mTOR pathway in IBC. IBC cells express IL-6 and IL-8 and recruit tumor activated macrophages (TAMs) that further induce IL-6, IL-8 and activate the JAK2/STAT3 pathway. We investigated the independent and combined activity of these pathways in IBC tissues. Methods: Archived tissues of 42 IBC pts and 13 controls (nl breast) were analyzed using IHC and scored by 3 independent pathologists. Results defined as: 0, 1+ = neg; 2+ = pos for activated mTOR (P-S6) and 0 = neg; 1+, 2+ = pos for activated nuclear JAK2/STAT3 (P-JAK2; P-STAT3), cytokine (IL-6), macrophage (mØ) infiltration (CD68) and TAM (CD163). Proportions of IBC cases with pos expression were compared with controls (Fishers exact tests). Clinical and survival data were obtained. Results: Median age at diagnosis: 46 yrs (31-62) in early-stage IBC [EIBC] (n=37) and 41 yrs (29-57) in pts with de novo metastatic IBC [MIBC] (n=5). In EIBC, 19/36: HER2+ (1 unk); 8/19: ER+/HER2+; 8/36: ER-/HER2-. In MIBC, all were ER- (1 unk) and 3/4 were HER2+ (1 unk). 88% Rx with neoadjuvant and/or adjuvant anthracycline and taxane w/o adjuvant trastuzumab. 24 pts died (5/5 MIBC). Median OS: 86 mo (95% CI lower 48 mo) for EIBC & 41 mo (95% CI 8-81 mo) for MIBC. Median RFS: 18 mo (95% CI 18-79 mo) for 23 pts (13 NED; 1 unk). All controls: neg for P-S6, JAK2, STAT3 and TAMs and 92% neg for mØ and IL-6. Proportion of IBC with pos expression when compared to controls listed in table (p <0.0001). Of 31 pts with complete biomarker data who were PS6+, 97% had activated JAK2, 58% had activated STAT3, 80% had strong mØ and TAM infiltration and 97% were IL6+. Conclusions: This is the first study that validates preclinical findings and shows a strong association between mTOR, cytokines, TAMs and JAK/STAT pathways in most IBC pt tissues. Findings suggest a key role for dual blockade of mTOR and JAK/STAT pathways in phase I trials.