Abstract
Brain metastasis is a devastating problem in patients with breast, lung and melanoma tumors. GRP94 and FN14 are predictive biomarkers over-expressed in primary breast carcinomas that metastasized in brain. To further validate these brain metastasis biomarkers, we performed a multicenter study including 318 patients with breast carcinomas. Among these patients, there were 138 patients with metastasis, of whom 84 had brain metastasis. The likelihood of developing brain metastasis increased by 5.24-fold (95%CI 2.83-9.71) and 2.55- (95%CI 1.52-4.3) in the presence of FN14 and GRP94, respectively. Moreover, FN14 was more sensitive than ErbB2 (38.27 vs. 24.68) with similar specificity (89.43 vs. 89.55) to predict brain metastasis and had identical prognostic value than triple negative patients (p < 0.0001). Furthermore, we used GRP94 and FN14 pathways and GUILD, a network-based disease-gene prioritization program, to pinpoint the genes likely to be therapeutic targets, which resulted in FN14 as the main modulator and thalidomide as the best scored drug. The treatment of mice with brain metastasis improves survival decreasing reactive astrocytes and angiogenesis, and down-regulate FN14 and its ligand TWEAK. In conclusion our results indicate that FN14 and GRP94 are prediction/prognosis markers which open up new possibilities for preventing/treating brain metastasis.
Highlights
Brain metastasis (BrM) occurs mainly after the diagnosis of systemic metastases in up to 30% of cancer patients [1, 2]
We took all of these parameters into account when evaluating the contribution of the previously defined breast cancer brain metastasis biomarkers (BCBrMBK): GRP94, TRAF2, factor-inducible protein 14 (FN14) and Inhibin [24]
This study is the first to report that fibroblast growth factor-inducible protein 14 (FN14) expression and GRP94 expression in a patient diagnosed with breast cancer (BC) indicates a high risk of brain metastasis (BrM) progression, offering the opportunity to develop therapeutic strategies either to prevent the disease or facilitate early detection
Summary
Brain metastasis (BrM) occurs mainly after the diagnosis of systemic metastases in up to 30% of cancer patients [1, 2]. The large numbers of differentially expressed genes in the five molecular subtypes of breast carcinoma confirm the diversity of the underlying biology [11]. These biomarkers include the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (ErbB2 or HER2). Known predictive factors for BrM are: (i) overexpression of ErbB2, (ii) lack of hormone receptor expression, (iii) triple-negative subtype (TNBC) with ER and PR-negative and normal ErbB2, (iv) patient age under 50 years and (v) the presence of positive regional lymph nodes and lung metastases [14, 15]. In a retrospective series of metastatic breast carcinoma (MBC) patients treated with trastuzumab, 52% of them succumbed to CNS progression the non-CNS disease was stable or responsive [16]
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