Abstract
MicroRNAs (miRNAs) are key regulators in immune surveillance and immune escape as well as modulators in the metastatic process of breast cancer cells. We evaluated the differential expression of plasma miR-10b, miR-19a, miR-20a, miR-126 and miR-155, which regulate immune response in breast cancer progression and we investigated their clinical relevance in the outcomes of breast cancer patients. Plasma samples were obtained from early (eBC; n = 140) and metastatic (mBC; n = 64) breast cancer patients before adjuvant or first-line chemotherapy, respectively. Plasma miRNA expression levels were assessed by qRT-PCR. We revealed a 4-miRNA panel consisted of miR-19a, miR-20a, miR-126, and miR-155 able to discriminate eBC from mBC patients with an AUC of 0.802 (p < 0.001). Survival analysis in eBC patients revealed that low miR-10b and miR-155 expression was associated with shorter disease free survival (disease free survival; p = 0.012 and p = 0.04, respectively) compared to high expression. Furthermore, miR-126 expression was associated with shorter overall survival (overall survival; p = 0.045). In multivariate analysis the number of infiltrated axillary lymph nodes and low miR-10b expression independently predicted for shorter DFS (HR: 2.538; p = 0.002 and HR: 1.943; p = 0.033, respectively) and axillary lymph nodes and low miR-126 for shorter OS (HR: 3.537; p = 0.001 and HR: 2.558; p = 0.018). In the subgroup of triple negative breast cancer (TNBC) patients, low miR-155 expression independently predicted for shorter DFS (HR: 5.056; p = 0.037). Accordingly in mBC, patients with low miR-10b expression had shorter progression free survival and OS compared to patients with high expression (p = 0.0017 and p = 0.042, respectively). In multivariate analysis, recurrent disease and low miR-10b expression independently predicted for shorter PFS (HR: 2.657; p = 0.001 and HR: 1.920; p = 0.017, respectively), whereas performance status two independently predicted for shorter OS (HR: 2.031; p = 0.03). In summary, deregulated expression of circulating miRNAs involved in tumor and immune cell interactions evaluated before adjuvant and 1st-line chemotherapy can distinguish disease status and emerge as independent predictors for outcomes of breast cancer patients.
Highlights
Metastatic dissemination remains the main cause of morbidity and mortality in patients with breast cancer (Riggio et al, 2021)
Tumor cells modulate the recruitment of tumor-associated macrophages (TAMs), T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSc) in the tumour microenvironment (Kitamura et al, 2015), suppressing the cytotoxic function of natural killer (NK) cells and CD8+ T cells through the expression of molecules such as programmed cell death ligand 1 (PDL1) and promoting tumor survival and metastatic potential (Kitamura et al, 2015)
Flow chart of the study and clinicopathological characteristics of early (n 140) and metastatic (n 64) breast cancer patients are presented in Figure 1and Table 1, respectively
Summary
Metastatic dissemination remains the main cause of morbidity and mortality in patients with breast cancer (Riggio et al, 2021). Despite the progress in diagnosis and treatment of early breast cancer, about 25% of patients are still at high risk for developing metastases in distant organs, whereas the survival rates of those with metastatic disease have only modestly improved during the last years (Caswell-Jin et al, 2018). According to the cancer immunoediting theory the immune system can influence tumor development through a three-step process: elimination, equilibrium and escape (Schreiber et al, 2011). Under the constant selective pressure from the immune system, cancer cells acquire genetic and epigenetic alterations that allow them to grow despite the ongoing immune response (Schreiber et al, 2011). Tumor cells modulate the recruitment of tumor-associated macrophages (TAMs), T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSc) in the tumour microenvironment (Kitamura et al, 2015), suppressing the cytotoxic function of natural killer (NK) cells and CD8+ T cells through the expression of molecules such as programmed cell death ligand 1 (PDL1) and promoting tumor survival and metastatic potential (Kitamura et al, 2015)
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