Abstract PD5-6: Sustained hyperactivated mTOR & JAK2/STAT3 pathways in inflammatory breast cancer (IBC): Evidence for mTOR plus JAK2 therapeutic targeting

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-12, Vol.73 (24_Supplement), p.PD5-6-PD5-6
• Main 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
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.SABCS13-PD5-6

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 compl