Abstract
IntroductionEffective 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.MethodsThe 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.ResultsThe 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.ConclusionsProfiles 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.
Highlights
Effective predictive biomarkers for selection of patients benefiting from adjuvant platinumbased chemotherapy in non-small cell lung cancer (NSCLC) are needed
Lung cancer account for 1.59 million deaths annually worldwide and 85% of cases are nonsmall cell lung cancer (NSCLC) [1]
Since some of the NSCLC patients receiving cisplatin do not benefit from the treatment, given the controversial results for stage 1B patients, and considering that some of stage 1A patients not receiving cisplatin might benefit from it, more effective predictive biomarkers for this treatment appear highly warranted
Summary
The model is based on in vitro cytotoxicity for each specific drug tested in the NCI60 cell line panel developed prior to the present study by Medical Prognosis Institute [20]. In this project, correlations of cytotoxicity to cisplatin and vinorelbine, respectively, were combined with the transcriptome of the 60 cell lines in the panel. The final signature consists of two sets of genes, features associated with sensitivity and features associated with resistance We tested both the mRNA and the miRNA transcriptomes in two separate profiles of each drug. The probes of the cisplatin profile were annotated to corresponding gene names and submitted to g:Profiler for functional interpretation and presented in S1 Doc are a subset of 73 genes that were positively correlated for association to pathways or gene ontologies and had significantly enriched BIOGRID interactions [26]
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