Use of a three-microRNA signature to discriminate prognostic groups in early-stage NSCLC patients in the IFCT-0002 trial.

Abstract

7007 Background: No survival differences was observed between any arms in the 528 early stage NSCLC randomized patients of the IFCT-0002 phase III trial comparing two chemotherapy timing, all pre- vs. peri-operative, and two regimens, CDDP-Gem vs. CBDCA-Pac (V. Westeel, ASCO 2009). We hypothesized that microRNA (miRNA) expression profile could discriminate prognostic groups in these patients. Methods: Total RNA was extracted from 277 paraffin-embedded surgical macrodissected specimens. Expression of 17 miRNAs was successfully analyzed by Taqman qRT-PCR in 276 (99%) samples. Multivariate analysis with Cox model for overall survival (OS) was validated with a two-step bootstrap resampling analysis. Results: Low miR210 (under median) miR21, and miR15a, (under first quartile) expression significantly predicted a better survival when adjusted for stage and number of administered cycles, the two clinical variables influencing OS in multivariate analysis. A model including the three miRNAs discriminates three prognostic groups: Group 1: patients with the three miRNAs under the defined cut-off (n=129), Group 2: among the remaining patients, patients with miR21 under Q1, independently of the status of the two other miRNAs (n=82), and Group 3: all remaining patients (n=65). In univariate analysis, Group 1 showed the best OS (> 83 months), Group 2 intermediate OS (66 months), and Group 3 the worse OS (36 months, p=0.001, log-rank test). Adjusted HRs for OS with Group 3 as reference were 0.445, 95%CI [0.290-0.682], p=0.0002 and 0.632, 95%CI [0.406-0.986], p=0.043 for Group 1 and 2, respectively. Harrell’s concordance index of 0.83, 95%CI [0.67-0.95] showed a good predictive accuracy. A first bootstrap with 300 random resampling showed the stability of the miR model which significantly predicted OS in 260 samples (86.7%). The reproducibility of the model was confirmed by a second similar bootstrap procedure, the c-indexes of the created models ranging from 0.74 to 0.85. Conclusions: A miRNA model associating mIR15a, mIR21, and mIR210, accurately discriminates three prognostic groups in early-stage NSCLC patients treated by perioperative chemotherapy.