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Molecular prediction of adjuvant cisplatin efficacy in Non-Small Cell Lung Cancer (NSCLC)-validation in two independent cohorts.

Molecular prediction of adjuvant cisplatin efficacy in Non-Small Cell Lung Cancer (NSCLC)-validation in two independent cohorts.
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Buhl IK, Santoni-Rugiu E, Ravn J, Hansen A, Christensen IJ, Jensen T, Pratt B, Askaa J, Jensen PB, Knudsen S, Sørensen JB,


Buhl IK, Santoni-Rugiu E, Ravn J, Hansen A, Christensen IJ, Jensen T, Pratt B, Askaa J, Jensen PB, Knudsen S, Sørensen JB, (click to view)

Buhl IK, Santoni-Rugiu E, Ravn J, Hansen A, Christensen IJ, Jensen T, Pratt B, Askaa J, Jensen PB, Knudsen S, Sørensen JB,

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PloS one 2018 03 2213(3) e0194609 doi 10.1371/journal.pone.0194609

Abstract
INTRODUCTION
Effective predictive biomarkers for selection of patients benefiting from adjuvant platinum-based chemotherapy in non-small cell lung cancer (NSCLC) are needed. Based on a previously validated methodology, molecular profiles of predicted sensitivity in two patient cohorts are presented.

METHODS
The profiles are correlations between in vitro sensitivity to cisplatin and vinorelbine and baseline mRNA expression of the 60 cell lines in the National Cancer Institute panel. An applied clinical samples filter focused the profiles to clinically relevant genes. The profiles were tested on 1) snap-frozen tumors from 133 patients with completely resected stage 1B-2 NSCLC randomized to adjuvant cisplatin and vinorelbine (ACV, n = 71) or no adjuvant treatment (OBS, n = 62) and 2) formalin-fixed paraffin-embedded (FFPE) tumors from 95 patients with completely resected stage 1A-3B NSCLC receiving adjuvant cisplatin and vinorelbine.

RESULTS
The combined cisplatin and vinorelbine profiles showed: 1) univariate Hazard Ratio (HR) for sensitive versus resistant of 0.265 (95% CI:0.079-0.889, p = 0.032) in the ACV cohort and a HR of 0.28 in a multivariate model (95% CI:0.08-1.04, p = 0.0573); 2) significant prediction at 3 year survival from surgery in univariate (HR = 0.138 (95% CI:0.035-0.537), p = 0.004) and multivariate analysis (HR = 0.14 (95% CI:0.030-0.6), p = 0.0081). No discrimination was found in the OBS cohort (HR = 1.328, p = 0.60). The cisplatin predictor alone had similar figures with 1) univariate HR of 0.37 (95% CI:0.12-1.15, p = 0.09) in the ACV cohort and 2) univariate HR of 0.14 (95% CI:0.03-0.59, p = 0.0076) to three years. Functional analysis on the cisplatin profile revealed a group of upregulated genes related to RNA splicing as a part of DNA damage repair and apoptosis.

CONCLUSIONS
Profiles derived from snap-frozen and FFPE NSCLC tissue were prognostic and predictive in the patients that received cisplatin and vinorelbine but not in the cohort that did not receive adjuvant treatment.

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