MicroRNAs (miRNAs) have been found to play an important role in breast cancer, functioning either as potential oncogenes or tumor suppressor genes, but their role in the prognosis of patients remains unclear. The aim of the present review study is to highlight recent preclinical and clinical studies performed on both circulating and tissue-specific miRNAs and their potential role as prognostic markers in breast cancer. We systematically searched the PubMed database to explore the prognostic value of miRNAs in breast cancer. After performing the literature search and review, 117 eligible studies were identified. We found that 110 aberrantly expressed miRNAs have been associated with prognosis in breast cancer. In conclusion, the collective data presented in this review indicate that miRNAs could serve as novel prognostic tools in breast cancer, while the clinical application of these findings has yet to be verified.

Circulating microRNAs (miRNAs) are key regulators of the crosstalk between tumor cells and immune response. In the present study, miRNAs (let-7c, miR-26a, miR-30d, miR-98, miR-195, miR-202) reported to be involved in the polarization of macrophages were examined for associations with the outcomes of non-small cell lung cancer (NSCLC) patients (N = 125) treated with first-line platinum-based chemotherapy. RT-qPCR was used to analyze miRNA expression levels in the plasma of patients prior to treatment. In our results, disease progression was correlated with high miR-202 expression (HR: 2.335; p = 0.040). Additionally, high miR-202 expression was characterized as an independent prognostic factor for shorter progression-free survival (PFS, HR: 1.564; p = 0.021) and overall survival (OS, HR: 1.558; p = 0.024). Moreover, high miR-202 independently predicted shorter OS (HR: 1.989; p = 0.008) in the non-squamous (non-SqCC) subgroup, and high miR-26a was correlated with shorter OS in the squamous (SqCC) subgroup (10.07 vs. 13.53 months, p = 0.033). The results of the present study propose that the expression levels of circulating miRNAs involved in macrophage polarization are correlated with survival measures in NSCLC patients, and their role as potential biomarkers merits further investigation.

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.

The outcome of patients with multiple myeloma (MM) is heterogeneous and the median survival of patients with symptomatic disease ranges from a few months to several years. Although the survival of MM patients has increased over the past 10 years, there is still a proportion of patients who die within a few months from the initiation of therapy, even when they are treated with the most contemporary drug regimens. Our aim was to identify the factors that are associated with early death among patients with symptomatic myeloma and explore whether incorporation of new therapies has also improved short-term outcome. We analyzed 509 consecutive patients that have been treated in a single center (Department of Clinical Therapeutics, Athens, Greece) from January 1994 to December 2012. All patients, irrespective of age or performance status (PS) who received at least one dose of therapy were included in the analysis. Median age of the patients was 69 years (range 31-92 years); 62% were older than 65 and 27% older than 75 years. Osteolytic bone disease (in plain X-rays) was present in 74% of the patients; 25% had ISS-1, 35.5% had ISS-2 and 39.5% ISS-3 disease. Elevated LDH >300 IU/L was present in 8%; 21% had severe renal impairment (eGFR<30 ml/min/1.73m2). Primary therapy with conventional chemotherapy (CC) was given in 25.5%, IMiDs-based (mainly thalidomide) in 48% and bortezomib-based regimens in 26.5% of the patients. Two-month, 6-month and one-year mortality was 6%, 13% and 18%, respectively. Age >75 years was strongly associated with higher rates of early mortality (2-month, 6-month and 1 year mortality was 8%, 11% and 21% vs. 4%, 5% and 10% for patients <75 years, p<0.001). Other factors associated with early mortality included PS ≥2 (2-month, 6-month and 1-year mortality were 9%, 13% and 23% vs. 2%, 3% and 7% for patients with PS≤1, p<0.001), anemia (Hb<10 g/dl), ISS-3 disease (2-month, 6-month and 1-year mortality were 12%, 16% and 28% vs. 3%, 4% and 11% for patients with ISS-2 vs. 1%, 2% and 2% for patients with ISS-1, p<0.001), platelet counts <130x109/L (p<0.001), or eGFR<30 ml/min/1.73m2 (p<0.001). Primary therapy with novel agents (thalidomide, bortezomib or lenalidomide) was associated with reduced early mortality: 2-month, 6-month and 1-year mortality rate was 10%, 14% and 22% for those who received CC vs. 5%, 8% and 16% for patients who received IMiDs-based therapy vs. 3%, 4% and 8% for patients who received bortezomib-based therapy (p<0.001). In multivariate analysis the strongest predictors of death within <2 months were age >75 years (HR: 3, 95% CI 1.25-7.3, p=0.014), PS >1 (HR: 2.88, 95% CI 1.02-8, p=0.045), while ISS-3 had marginal independent significance (HR: 8, 95% CI 0.99-67, p=0.051). Importantly, the upfront use of bortezomib-based regimens (HR: 0.21 95% CI 0.06-0.73, p<0.014) or IMiDs-based regimens (HR: 0.27, 95% CI 0.1-0.68) reduced the risk of early death over CC. However, there was a strong interaction between the type of therapy and age >75 years, as only a minority of patients >75 years received bortezomib-based therapy. When this interaction was accounted for in the model, then it was significant (p=0.041), indicating that age >75 years was associated with early death also due to the reduced use of bortezomib (but not of IMiDs). In multivariate analysis for predictors of death within the first 12 months from initiation of therapy age >75 years (HR: 4.125, 95% CI 2.2-7.7,p<0.001), PS >1 (HR: 2.5, 95% CI 1.33-4.7, p=0.005), ISS-3 (HR: 7.5, 95% CI 2.44-23, p<0.001) and LDH ≥300 IU/L (HR: 3.5, 95% CI 1.5-7.9, p<0.003) were associated with increased risk, while the upfront use of bortezomib-based regimens (HR: 0.26, 95% CI 0.11-0.64, p=0.003) or IMiDs-based regimens (HR: 0.38, 95% CI0.19-0.75, p=0.005) reduced the risk of early death over CC. However, if patients who died within the first two months were excluded, then the type of primary therapy was not significant. The above results indicate that host characteristics (age, PS) are crucial predictors of very early death (<2 months) but the use of very active therapy is crucial for the rapid disease control and the management of early complications, like renal impairment, in order to reduce very early mortality. However, later in the course of the disease, it is the disease characteristics, which are depicted in ISS stage and LDH levels, along with patient’s characteristics (age, PS) that are the major predictors of early death (within 12 months). Disclosures: No relevant conflicts of interest to declare.