Work

Early2 factor (E2F) deregulation is a prognostic and predictive biomarker in lung adenocarcinoma

Year: 2016

Type: article

Abstract: // Lu Chen 1,* , Courtney A. Kurtyka 1,* , Eric A. Welsh 1,* , Jason I. Rivera 1,* , Brienne E. Engel 2 , Teresita Muñoz-Antonia 3 , Sean J. Yoder 4 , Steven A. Eschrich 1 , Ben C. Creelan 5 , Alberto A. Chiappori 5 , Jhanelle E. Gray 5 , Jose Luis Ramirez 6 , Rafael Rosell 6 , Matthew B. Schabath 7 , Eric B. Haura 5 , Dung-Tsa Chen 1 and W. Douglas Cress 2 1 Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA 2 Cancer Biology and Evolution, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA 3 Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA 4 Molecular Genomics Core Facility, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA 5 Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA 6 Cancer Biology & Precision Medicine Program, Catalan Institute of Oncology, Badalona, Barcelona, Spain 7 Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA * Co-first authors Correspondence to: Dung-Tsa Chen, email: // W. Douglas Cress, email: // Keywords : lung adenocarcinoma, adjuvant chemotherapy, E2F, predictive biomarker, prognostic biomarker Received : September 28, 2016 Accepted : October 07, 2016 Published : October 14, 2016 Abstract Clinicians routinely prescribe adjuvant chemotherapy (ACT) for resected non-small cell lung cancer patients. However, ACT only improves five-year disease-free survival in stage I-III non-small cell lung cancer by 5-15%, with most patients deriving no benefit. Herein, deregulation of the E2F pathway was explored as a biomarker in lung adenocarcinoma patients. An E2F pathway scoring system, based on 74 E2F-regulated genes, was trained for RNA from two platforms: fresh-frozen (FF) or formalin-fixed paraffin-embedded (FFPE) tissues. The E2F score was tested as a prognostic biomarker in five FF-based cohorts and two FFPE-based cohorts. The E2F score was tested as a predictive biomarker in two randomized clinical trials; JBR10 and the NATCH (Neo-Adjuvant Taxol-Carboplatin Hope) trial. The E2F score was prognostic in untreated patients in all seven datasets examined ( p < 0.05). Stage-specific analysis of combined cohorts demonstrated that the E2F score was prognostic in stage I patients ( p = 0.0495 to <0.001; hazard ratio, HR, =2.04- 2.22) with a similar trend in other stages. The E2F score was strongly predictive in stage II patients from the two combined randomized clinical trials with a significant differential treatment effect ( p = 0.015). Specifically, ACT improved survival in stage II patients with high E2F ( p = 0.01; HR= 0.21). The 5-year survival increased from 18% to 81%. In contrast, in patients with low E2F, 5-year survival was 57% in untreated patients and 41% in ACT-treated patients with a HR of 1.55 ( p = 0.47). In summary, the E2F score provides valuable prognostic information for Stage I and predictive information for Stage II lung adenocarcinoma patients and should be further explored as a decision support tool for their treatment.

Source: Oncotarget

DOI: 10.18632/oncotarget.12672