Jhaveri Komal, Teplinsky Eleonora, Silvera Deborah, Valeta-Magara Amanda, Arju Rezina, Giashuddin Shah, Sarfraz Yasmeen, Alexander Melissa, Darvishian Farbod, Levine Paul H, Hashmi Salman, Zolfaghari Ladan, Hoffman Heather J, Singh Baljit, Goldberg Judith D, Hochman Tsivia, Formenti Silvia, Esteva Francisco J, Moran Meena S, Schneider Robert J
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY.
Division of Hematology & Medical Oncology, Department of Medicine, New York University School of Medicine, New York, NY.
Clin Breast Cancer. 2016 Apr;16(2):113-22.e1. doi: 10.1016/j.clbc.2015.11.006. Epub 2015 Dec 1.
Inflammatory breast cancer (IBC) is an aggressive and rare cancer with a poor prognosis and a need for novel targeted therapeutic strategies. Preclinical IBC data showed strong activation of the phosphatidylinositide-3-kinase/mammalian target of rapamycin (mTOR) and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways, and expression of inflammatory cytokines and tumor-associated macrophages (TAMs).
Archival tumor tissue from 3 disease types (IBC treated with neoadjuvant chemotherapy [NAC], n = 45; invasive ductal carcinoma [IDC] treated with NAC [n = 24; 'treated IDC'; and untreated IDC [n = 27; 'untreated IDC']) was analyzed for the expression of biomarkers phospho-S6 (pS6) (mTOR), phospho-JAK2 (pJAK2), pSTAT3, interleukin (IL)-6, CD68 (monocytes, macrophages), and CD163 (TAMs). Surrounding nontumor tissue was also analyzed.
Biomarker levels and surrogate activity according to site-specific phosphorylation were shown in the tumor tissue of all 3 disease types but were greatest in IBC and treated IDC and least in untreated IDC for pS6, pJAK2, pSTAT3, and IL-6. Of 37 IBC patients with complete biomarker data available, 100% were pS6-positive and 95% were pJAK2-positive. In nontumor tissue, biomarker levels were observed in all groups but were generally greatest in untreated IDC and least in IBC, except for JAK2.
IBC and treated IDC display similar levels of mTOR and JAK2 biomarker activation, which suggests a potential mechanism of resistance after NAC. Biomarker levels in surrounding nontumor tissue suggested that the stroma might be activated by chemotherapy and resembles the oncogenic tumor-promoting environment. Activation of pS6 and pJAK2 in IBC might support dual targeting of the mTOR and JAK/STAT pathways, and the need for prospective studies to investigate combined targeted therapies in IBC.
炎性乳腺癌（IBC）是一种侵袭性强且罕见的癌症，预后较差，需要新的靶向治疗策略。临床前IBC数据显示磷脂酰肌醇-3-激酶/雷帕霉素哺乳动物靶点（mTOR）和Janus激酶（JAK）/信号转导及转录激活因子（STAT）通路强烈激活，以及炎性细胞因子和肿瘤相关巨噬细胞（TAM）的表达。
分析了来自3种疾病类型（接受新辅助化疗[NAC]治疗的IBC，n = 45；接受NAC治疗的浸润性导管癌[IDC][n = 24；“治疗的IDC”]；以及未治疗的IDC[n = 27；“未治疗的IDC”]）的存档肿瘤组织中生物标志物磷酸化S6（pS6）（mTOR）、磷酸化JAK2（pJAK2）、pSTAT3、白细胞介素（IL）-6、CD68（单核细胞、巨噬细胞）和CD163（TAM）的表达。还分析了周围的非肿瘤组织。
所有3种疾病类型的肿瘤组织中均显示了根据位点特异性磷酸化的生物标志物水平和替代活性，但对于pS6、pJAK2、pSTAT3和IL-6，在IBC和治疗的IDC中最高，在未治疗的IDC中最低。在有完整生物标志物数据的37例IBC患者中，100%为pS6阳性，95%为pJAK2阳性。在非肿瘤组织中，所有组均观察到生物标志物水平，但除JAK2外，通常在未治疗的IDC中最高，在IBC中最低。
IBC和治疗的IDC显示出相似水平的mTOR和JAK2生物标志物激活，这提示了NAC后潜在的耐药机制。周围非肿瘤组织中的生物标志物水平表明，基质可能被化疗激活，类似于致癌的肿瘤促进环境。IBC中pS6和pJAK2的激活可能支持对mTOR和JAK/STAT通路的双重靶向，以及需要进行前瞻性研究以探讨IBC中的联合靶向治疗。
