Elevated Level of Nerve Growth Factor (NGF) in Serum-Derived Exosomes Predicts Poor Survival in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy

SIMPLE SUMMARY: Exosomes and cytokines play crucial roles in the process of tumor progression. Recent studies have reported that cytokines can be packaged into exosomes, leading to drug resistance. The aim of this study is to evaluate the potential value of cytokines in both serum and exosomes as prognostic biomarkers of long-term outcomes in patients with breast cancer treated with neoadjuvant chemotherapy. We observed significant differences in expression patterns between serum cytokines and exosomal cytokines. Elevated levels of serum IP-10, serum MMP-1, and exosomal NGF were associated with poor overall survival. In multivariate analysis, exosomal NGF was an independent prognostic factor for overall survival. These findings suggest that exosomal NGF is useful for identifying patients with poor survival outcomes. ABSTRACT: Neoadjuvant chemotherapy (NAC) is a standard treatment strategy for patients with locally advanced breast cancer (LABC). However, there are no established predictors of chemosensitivity and survival in LABC patients who undergo NAC. Many studies have demonstrated that exosomes and cytokines are important players in intercellular communication between tumors and their environments, and are involved in chemotherapy resistance. Recently, it was reported that cytokines can be packaged into exosomes, but whether exosomal cytokines serve as biomarkers in breast cancer patients is still unclear. In this study, we examined the roles of cytokines in both serum and exosomes as prognostic biomarkers for long-term outcomes in patients with breast cancer who undergo NAC. We isolated exosomes from the blood of 129 patients with early breast cancer who were receiving neoadjuvant chemotherapy between 2008 and 2011 at Samsung Medical Center. The levels of cytokines and growth factors in serum and exosomes were measured with ProcartaPlex immune-related panels. We investigated correlations between clinic-pathologic variables and patient survival, and Cox proportional hazards regression analysis was performed for prognostic evaluation. We detected significant differences in expression patterns between serum cytokines and exosomal cytokines. In both serum and exosomes, many cytokines were positively correlated with age. In univariate analysis, patients with high serum IP-10, serum MMP-1, and exosomal NGF had shorter overall survival. Exosomal NGF showed significantly poorer overall survival in multivariate analysis. These findings suggest that exosomal NGF is useful for identifying patients with poor survival outcomes.