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

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.

• Authors: Lu Chen, Courtney A Kurtyka, Eric A Welsh, Jason I Rivera, Brienne E Engel, Teresita Muñoz-Antonia, Sean J Yoder, Steven A Eschrich, Ben C Creelan, Alberto A Chiappori, Jhanelle E Gray, Jose Luis Ramirez, Rafael Rosell, Matthew B Schabath, Eric B Haura, Dung-Tsa Chen, W Douglas Cress
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 50 Pg. 82254-82265 (Dec 13 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27756884 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial)

Chemical References

• Biomarkers, Tumor
• E2F Transcription Factors
• Carboplatin
• Paclitaxel

Topics

• Adenocarcinoma (drug therapy, genetics, mortality, pathology)
• Adenocarcinoma of Lung
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers, Tumor (genetics)
• Carboplatin (administration & dosage)
• Cell Line, Tumor
• Chemotherapy, Adjuvant
• E2F Transcription Factors (genetics)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Kaplan-Meier Estimate
• Lung Neoplasms (drug therapy, genetics, mortality, pathology)
• Neoadjuvant Therapy
• Neoplasm Staging
• Paclitaxel (administration & dosage)
• Precision Medicine
• Predictive Value of Tests
• Proportional Hazards Models
• Time Factors
• Transcriptome
• Treatment Outcome