title: 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.affiliation: Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Kurtyka
authors.affiliation: Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Welsh
authors.affiliation: Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
authors.forename: Jason I
authors.initials: JI
authors.lastname: Rivera
authors.affiliation: Cancer Biology and Evolution, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
authors.forename: Brienne E
authors.initials: BE
authors.lastname: Engel
authors.affiliation: Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
authors.forename: Teresita
authors.initials: T
authors.lastname: Muñoz-Antonia
authors.affiliation: Molecular Genomics Core Facility, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Yoder
authors.affiliation: Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Eschrich
authors.affiliation: Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
authors.forename: Ben C
authors.initials: BC
authors.lastname: Creelan
authors.affiliation: Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
authors.forename: Alberto A
authors.initials: AA
authors.lastname: Chiappori
authors.affiliation: Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
authors.forename: Jhanelle E
authors.initials: JE
authors.lastname: Gray
authors.affiliation: Cancer Biology & Precision Medicine Program, Catalan Institute of Oncology, Badalona, Barcelona, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Ramirez
authors.affiliation: Cancer Biology & Precision Medicine Program, Catalan Institute of Oncology, Badalona, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Rosell
authors.affiliation: Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Schabath
authors.affiliation: Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Haura
authors.affiliation: Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
authors.forename: Dung-Tsa
authors.initials: DT
authors.lastname: Chen
authors.affiliation: Cancer Biology and Evolution, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
authors.forename: W Douglas
authors.initials: WD
authors.lastname: Cress
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D016190:Carboplatin / Q000008:administration & dosage; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D050684:E2F Transcription Factors / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D057285:Precision Medicine; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D013997:Time Factors; D059467:Transcriptome; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D050684:E2F Transcription Factors; D016190:Carboplatin; D017239:Paclitaxel
keywords: E2F; adjuvant chemotherapy; lung adenocarcinoma; predictive biomarker; prognostic biomarker