Abstract P4-07-15: Prognostic impact of miR-18a expression in residual tumor after neoadjuvant chemotherapy for locally advanced breast cancer
Authors: Luengo-Gil G , González-Conejero R , Chaves-Benito A , Soler-Sánchez G , González-Billalabeitia E , Pérez-Henarejos S , García-Martínez H , Arroyo-Rodríguez A , Vicente V , Ayala-de la Peña F 
Published: August 2014

Abstract
Background: microRNAs (miRNAs) are small ribonucleic acids that regulate protein expression through gene silencing mechanisms and show differential expression between cancer subtypes. Several studies have demonstrated that over- or under-expression of miRNA levels in tumors can modulate the expression levels of their gene/protein targets and thus their behavior. In breast cancer, the members of cluster miR-17-92 increase their expression levels as the histological grade increases, behaving like an oncogene, and are preferentially expressed in basal-like carcinomas. Moreover, mature components of this cluster are involved in estrogen receptor pathways and epithelial-mesenchymal transition, which suggest their implication in resistance to chemotherapy. The aim of this study was to determine the prognostic impact of miR-18a expression in the residual (resistant-to-treatment) tumor after neoadjuvant chemotherapy (nQT) in patients with locally advanced breast cancer (BC).
Methods: Small RNA was isolated from FFPE samples of post-chemotherapy residual tumor in patients without pathological complete response (pCR). Quantification of miR-18a was performed by RT-qPCR. Expression levels were determined by 2-DDCt method using snRNAU6 as endogenous control. We used the quartiles of expression as cutoff point. Association of miR-18a levels with clinical and pathological characteristics was evaluated with non-parametric tests. Kaplan-Meier curves, log-rank test and Cox proportional hazard regression multivariate models were used for disease free (DFS) and overall (OS) survival analysis. Statistical analysis was performed with SPSS 18.0 software.
Results: 121 consecutive women with invasive BC were included, mostly with stages IIB (28%) or IIIA-C (56.4%). Patients were immunohistochemically (IHC) classified as Her2- hormone-sensitive (HS) in 50.4% of cases; other phenotypes: Her2+ HS, 13.2%; Her2+ non-HS, 10.7%; triple negative, 21.5%. Treatment included sequential anthracyclines and taxanes (80.4% docetaxel) and a pCR was obtained in 17.4% of patients. Median overall survival (OS) and disease free survival (DFS) were not reached after a median follow-up of 60 months. High (above the median) expression levels of miR-18a in post-chemotherapy residual tumor were associated with pre-treatment grade 3 (p = 0.008), cN2-3 (p = 0.004), non-HS (p = 0.006) and triple negative phenotype (p = 0.01). No other associations with clinical or pathologic tumor characteristics (stage, HER2NEU overexpression) were found. High expression levels of miR-18a in residual tumors were also associated with reduced DFS and OS (log-rank test; p = 0.004 and p = 0.041 respectively). This negative prognostic impact was also confirmed for DFS in a multivariate analysis that included IHC phenotype and ypN+ (Table 1).
Table 1 OR95%CIPPhenotype1.571.11-2.230.010ypN+7.291.67-31.800.008miR-18a high3.091.01-9.410.047
Conclusion: High expression levels of miR-18a in chemotherapy-resistant residual breast cancer associates with pre-treatment aggressive biological characteristics and independently predicts disease recurrence. Our results suggest that post-treatment miR-18a might serve as a marker of treatment resistance and as a new target for BC treatment.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-07-15.