Abstract 171: Pre-miR-518b and pre-miR-598, novel serum biomarkers of de novo chemoresistance in advanced or unresectable NSCLC
Authors: Cherni Irene , Sima Chao , Ranade Aarati R. , Genuis Emerson , Butts Charles A. , Damaraju Sambasivarao , Reiman Anthony , Weiss Glen J. 
Published: June 2012

Background: Dysregulation of microRNAs (miRNAs) has been widely implicated in a variety of cancers and have been recognized as prognostic and/or predictive biomarkers. Lack of a standard method for stratifying advanced-stage non-small cell lung cancer (NSCLC) patients receiving platinum combination therapy often results in a number of patients that do not derive benefit yet are still exposed to treatment toxicity. We hypothesized that miRNAs in pre-treatment serum and/or plasma could be used to differentiate NSCLC patients who would have disease progression (PD) to first-line carboplatin and gemcitabine chemotherapy at first response assessment.

Methods: miRNA array profiling containing probes in triplicate for 900 mature miRNAs (Sanger miRBASE v13.0 released in March 2009) and 450 precursor (pre-) miRNAs along with positive and negative control probes was performed on total RNA isolated from the pre-treatment serum and plasma of 24 advanced or unresectable NSCLC patients who went on to receive first-line carboplatin and gemcitabine chemotherapy. SAM data analysis was applied to find significantly differentially-expressed miRNAs in one condition (PD at first radiologic response) in contrast to another (those without disease progression [nonPD]). Data was normalized to U6 small nuclear RNA and the top differentially-expressed miRNAs were identified based on fold change, p-values, q-values, and false discovery rates. Differentially-expressed miRNAs were validated by quantitative PCR. Single validated candidates or combinations thereof were selected based on specificity and sensitivity to segregate patients with PD vs. nonPD. Correlations for clinical parameters with candidate miRNA were also assessed.

Results: Four miRNAs were identified using miRNA microarray as potential candidate qualifiers. Two of them, pre-miR-518b and pre-miR-598, were validated in a qPCR assay and were shown to be significantly over-expressed in serum of PD patients. ROC curves plotting a combination of these two pre-miRNAs were able to discriminate between PD vs. nonPD patients with 83% sensitivity and 72% specificity. No significant correlation of these two pre-miRNAs was observed with clinical parameters such as age, gender, histology, smoking status, or overall survival. No significant plasma miRNA candidates were identified.

Conclusion: Serum miRNAs may serve as a proof-of-concept screening tool in predicting chemoresistance to platinum-based combination chemotherapy. This is an important step towards personalized medicine and could enable stratification of patients to treatment options thus reducing exposure to specific toxic chemotherapy agents that in the end result would not benefit the patient.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 171. doi:10.1158/1538-7445.AM2011-171