It is well-known that microRNAs (miRNAs) are critical mediators of initiation and disease progression in many human cancers. Rectal cancer is a highly prevalent tumor, accounting for around one third of newly diagnosed colorectal cancers. The usefulness of miRNAs as clinical biomarkers predictive of the outcome and response to chemoradiotherapy has been well-reported for rectal cancer. However, the existing literature on their functional and therapeutic impact needs to be put in context to clarify their role in disease pathogenesis. Therfore, this review is focused on the functional relevance of miRNAs as key regulators of signaling pathways in rectal cancer and their potential therapeutic value as novel molecular targets in this disease.

The standard treatment for patients with locally advanced colorectal cancer (LARC) is neoadjuvant 5-fluorouracil (5-FU) based chemoradiotherapy (CRT) followed by surgical mesorectal excision. However, the lack of response to this preoperative treatment strongly compromises patient outcomes and leads to surgical delays and undesired toxicities in those non-responder cases. Thus, the identification of effective and robust biomarkers to predict response to preoperative CRT represents an urgent need in the current clinical management of LARC. The oncomiR microRNA-19b (miR-19b) has been reported to functionally play oncogenic roles in colorectal cancer (CRC) cells as well as regulate 5-FU sensitivity and determine outcome in CRC patients. However, its clinical impact in LARC has not been previously investigated. Here, we show that miR-19b deregulation is a common event in this disease, and its decreased expression significantly associates with lower tumor size after CRT (p = 0.003), early pathological stage (p = 0.003), and absence of recurrence (p = 0.001) in LARC patients. Interestingly, low miR-19b expression shows a predictive value of better response to neoajuvant CRT (p < 0.001), and the subgroup of LARC patients with low miR-19b levels have a markedly longer overall (p = 0.003) and event-free survival (p = 0.023). Finally, multivariate analyses determined that miR-19b independently predicts both patient outcome and response to preoperative CRT, highlighting its potential clinical usefulness in the management of LARC patients.

The identification of robust prognostic markers still represents a need in locally advanced rectal cancer (LARC). MicroRNAs (miRs) have progressively emerged as promising circulating markers, overcoming some limitations that traditional biopsy comprises. Tissue miR-199b deregulation has been reported to predict outcome and response to neoadjuvant chemoradiotherapy (nCRT) in LARC, and was also found to be associated with disease progression in colorectal cancer. However, its biological and clinical relevance remains to be fully clarified. Thus, we observed here that miR-199b regulates cell migration, aggressiveness, and cell growth, and inhibits colonosphere formation and induces caspase-dependent apoptosis. Moreover, miR-199b expression was quantified by real-time PCR in plasma samples from LARC patients and its downregulation was observed in 22.7% of cases. This alteration was found to be associated with higher tumor size (p = 0.002) and pathological stage (p = 0.020) after nCRT. Notably, we observed substantially lower global miR-199b expression associated with patient downstaging (p = 0.009), as well as in non-responders compared to those cases who responded to nCRT in both pre- (p = 0.003) and post-treatment samples (p = 0.038). In concordance, we found that miR-199b served as a predictor marker of response to neoadjuvant therapy in our cohort (p = 0.011). Altogether, our findings here demonstrate the functional relevance of miR-199b in this disease and its potential value as a novel circulating marker in LARC.

E15556 Background: It has been recently reported that miR-148a promotes hepatocytic differentiation and its expression levels correlates with hepatocytic markers such as the hepatocyte-specific miR-122. Moreover, miR-148a is downregulated in hepatocarcinoma cells and its restoration impaires tumor growth, reduces liver fibrosis and induces an increased hepatic differentiated phenotype in vivo. The liver represents the most common metastatic niche in colorectal (CRC) and based on these novel findings we hypothesized that miR-148a could be playing a relevant role in the establishment of liver metastasis. Although little is known about the significance of miR-148a in CRC, some data in the literature would suggest its tumor suppressor role. Methods: We analyzed miR-148a in an initial set of 17 CRC patients with paired primary and metastatic tissues. To measure miR expression levels in tumor samples we performed real‐time RT‐PCR on formalin‐fixed paraffin‐embedded (FFPE). To further investigate our hypothesis we also analyzed in our patient cohort the expression of the hepatocyte-specific miR-122. Results: We found no changes in miR-148a expression between primary and metastatic samples from 5 CRC patients with lung metastasis (p = 0.225). However, we observed that miR-148a was overexpressed in the metastatic tissues of those 12 CRC cases with liver metastasis (p = 0.019). Finally, MiR-122 was found markedly overexpressed in CRC liver metastases compared to the paired primary tumors (p < 0.001). Conclusions: Our results would suggest that restoration of miR-148a levels is a relevant molecular event that contributes to the establishment of the metastatic CRC cell in the liver. The short number of patients included is a limitation of this study. Thus, the potential role of miR-148a in CRC liver metastasis has to be further confirmed in forthcoming studies.

E12007 Background: Breast cancer prognosis is influenced by several factors including Ki67 expression which may have a predictive role in luminal breast cancer patients. The aim of this study was to assess the value of Ki67 in breast cancers with positive hormonal receptors and HER2 overexpressed and to evaluate its impact on survival. Methods: Seventy eight consecutive patients diagnosed with locally advanced HER2 positive breast cancer who were treated with adjuvant therapy based on HER2 treatment were selected for this study (2004-2014). The adjuvant chemotherapy schemes were 44% TCH, 16% FEC, 11% AC/T and 29% other therapies. The median of followup was 68 months. Tumor proliferation was assessed immunohistochemically by Ki67 expression and calculated as percentage of stained tumor cells from this cohort previous to adjuvant chemotherapy administration and the results obtained were correlated with disease status and outcome. Results: High proliferation defined as a percentage > 15 of tumor cells was observed in 69% of the breast cancer patients cases. High proliferation significantly predicted longer overall survival (OS) (Log rank 0,012). At 10 years of follow-up, 93% of the patients with KI67 high expression were alive versus 43% of patients without overexpression. Multivariate analysis confirmed the clinical significance of Ki67 predicting OS for luminal HER2 breast cancer patients (p 0,04 y HR 9,6). Conclusions: High proliferation identifies a setting of luminal-B HER2+ subtype breast cancer patients with a significantly longer overall survival.