Early2 factor (E2F) deregulation is a prognostic and predictive biomarker in lung adenocarcinoma
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Lu Chen1,*, Courtney A. Kurtyka1,*, Eric A. Welsh1,*, Jason I. Rivera1,*, Brienne E. Engel2, Teresita Muñoz-Antonia3, Sean J. Yoder4, Steven A. Eschrich1, Ben C. Creelan5, Alberto A. Chiappori5, Jhanelle E. Gray5, Jose Luis Ramirez6, Rafael Rosell6, Matthew B. Schabath7, Eric B. Haura5, Dung-Tsa Chen1 and W. Douglas Cress2
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
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
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.
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