Abstract PD5-6: Sustained hyperactivated mTOR & JAK2/STAT3 pathways in inflammatory breast cancer (IBC): Evidence for mTOR plus JAK2 therapeutic targeting
Authors: Jhaveri K , Teplinsky E , Arzu R , Giashuddin S , Sarfraz Y , Alexander M , Darvishian F , Silvera D , Levine PH , Hashmi S , Hoffman HJ , Paul L , Singh B , Goldberg JD , Hochman T , Formenti S , Valeta A , Moran MS , Schneider RJ 
Published: August 2014

Abstract
Background: IBC is an aggressive form of breast cancer with poor prognosis. Combined multi-modality therapy results in a 5 year OS of 30%, underscoring the unmet need for targeted therapy. Our preclinical research in cell lines & xenograft tumor models has identified a role for hyper-activated PI3K/mTOR signaling in IBC. IBC cells express IL-6 and IL-8, which recruit tumor activated macrophages (TAMs) that further induce inflammatory cytokines and activate the JAK2/STAT3 pathway. We investigated the independent and combined activity of these pathways in IBC patient tissues.
Methods: Archived tissue specimens of 42 IBC patients (dx 1999-2009) and 27 non-IBC patients (dx 2001-2005) with invasive ductal carcinoma (IDC) were obtained. Surrounding non-tumor normal tissue from IBC (companion controls) was also utilized. All specimens were analyzed using immunohistochemistry (IHC) and scored by 3 independent pathologists. Results were defined as 0 = negative; 1+,2+ = positive for activated mTOR (P-S6); activated JAK2/STAT3 (P-JAK2; P-STAT3); cytokine (IL-6); macrophage infiltration (CD68) and TAM (CD163). Proportions of IBC cases with positive expression were compared with non-IBC cases (Fisher's exact test) & companion controls (McNemar's test). Clinical & survival data were obtained.
Results: Median age at diagnosis: 46 yrs (31-62) in early stage IBC [EIBC] (n = 37) & 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) & 3/4 were HER2+ (1 unk). 88% were rx with neoadjuvant &/or adjuvant anthracycline & taxane w/o adjuvant trastuzumab. There were 24 pt deaths (5/5 MIBC). Median f/u for EIBC: 6.3 yrs and for MIBC: 3.4 yrs. Median OS: 81.4 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). The non-IBC patients were all stage 2-3 with median age at diagnosis: 58 yrs (39-94). 19/27: ER+; 7/25 HER2+ (2 unk); 15/25 ER+/HER2-; 3/25 ER-/HER2-. 78% were rx with adjuvant anthracycline & taxane, 4% were rx with FEC and 18% did not receive adjuvant chemotherapy. 18% received adjuvant trastuzumab. Median f/u: 8.0 yrs. Median OS: not yet reached and median RFS: 111.3 mo (95% CI lower 34.5 mo). EIBC cases were compared with non-IBC cases & companion controls (Table 1). PS6, pJAK2 and pSTAT3 expression was significantly increased in IBC compared to non-IBC. Of the 29 EIBC patients with complete biomarker data who were PS6+, 28/29 (97%) were JAK2+, 15/29 (52%) were STAT3+, 26/29 (90%) were CD68+, 20/29 (69%) were CD163+ and 28/29 (97%) were IL6+.
Conclusion: This is the first study to validate preclinical findings & show a strong co-association between hyper-activation of mTOR & JAK/STAT pathways in most IBC patient tumors when compared to surrounding non-tumor tissue and non-IBC (IDC) tumors and tissues. These findings suggest a key role for dual blockade of mTOR & JAK/STAT pathways for IBC in phase I trials.
BiomarkerMcNemars p-value: Early Stage IBC vs companion controls (N = 37)Fishers p-value: Early stage IBC (N = 37)vs non-IBC (N = 27)PS6&lt;0.00010.0315pJAK2&lt;0.0001&lt;0.0001pSTAT30.0003&lt;0.0001CD163&lt;0.00010.0908CD68&lt;0.00010.0582IL60.00030.3882
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD5-6.