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5 protein-based signature for resectable lung squamous cell carcinoma improves the prognostic performance of the TNM staging
  1. Elena Martínez-Terroba1,2,
  2. Carmen Behrens3,
  3. Jackeline Agorreta1,2,4,5,
  4. Eduard Monsó6,7,
  5. Laura Millares6,7,
  6. Enriqueta Felip8,
  7. Rafael Rosell9,
  8. José Luis Ramirez9,
  9. Ana Remirez1,
  10. Wenceslao Torre4,10,
  11. Ignacio Gil-Bazo1,4,5,11,
  12. Miguel A Idoate2,4,5,12,
  13. Juan P de-Torres4,5,13,
  14. Ruben Pio1,4,5,14,
  15. Ignacio I Wistuba3,15,
  16. María J Pajares1,2,4,5,
  17. Luis M Montuenga1,2,4,5
  1. 1 Program in Solid Tumors, CIMA, Pamplona, Spain
  2. 2 Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
  3. 3 Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  4. 4 Navarra Health Research Institute (IDISNA), Pamplona, Spain
  5. 5 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
  6. 6 Neumology Service, Parc Taulí Universitary Hospital, Sabadell, Spain
  7. 7 CIBER de Enfermedades Respiratorias-CIBERES, Instituto de Salud Carlos III, Madrid, Spain
  8. 8 Vall d’Hebron University Hospital, Institute of Oncology, Barcelona, Spain
  9. 9 Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain
  10. 10 Department of Thoracic Surgery, Clínica Universidad de Navarra, Pamplona, Spain
  11. 11 Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain
  12. 12 Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain
  13. 13 Department of Neumology, Clínica Universidad de Navarra, Pamplona, Spain
  14. 14 Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
  15. 15 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  1. Correspondence to Dr Jackeline Agorreta and Professor Luis M Montuenga, Program in Solid Tumors, Center for Applied Medical Research (CIMA),Pamplona 31008, Spain; jagorreta{at}, lmontuenga{at}


Introduction Prognostic biomarkers have been very elusive in the lung squamous cell carcinoma (SCC) and none is currently being used in the clinical setting. We aimed to identify and validate the clinical utility of a protein-based prognostic signature to stratify patients with early lung SCC according to their risk of recurrence or death.

Methods Patients were staged following the new International Association for the Study of Lung Cancer (IASLC) staging criteria (eighth edition, 2018). Three independent retrospective cohorts of 117, 96 and 105 patients with lung SCC were analysed to develop and validate a prognostic signature based on immunohistochemistry for five proteins.

Results We identified a five protein-based signature whose prognostic index (PI) was an independent and significant predictor of disease-free survival (DFS) (p<0.001; HR=4.06, 95% CI 2.18 to 7.56) and overall survival (OS) (p=0.004; HR=2.38, 95% CI 1.32 to 4.31). The prognostic capability of PI was confirmed in an external multi-institutional cohort for DFS (p=0.042; HR=2.01, 95% CI 1.03 to 3.94) and for OS (p=0.031; HR=2.29, 95% CI 1.08 to 4.86). Moreover, PI added complementary information to the newly established IASLC TNM 8th edition staging system. A combined prognostic model including both molecular and anatomical (TNM) criteria improved the risk stratification in both cohorts (p<0.05).

Conclusion We have identified and validated a clinically feasible protein-based prognostic model that complements the updated TNM system allowing more accurate risk stratification. This signature may be used as an advantageous tool to improve the clinical management of the patients, allowing the reduction of lung SCC mortality through a more accurate knowledge of the patient’s potential outcome.

  • signature
  • immunohistochemistry
  • squamous cell carcinoma
  • disease-free survival
  • overall survival
  • clinical utility
  • prognosis
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  • Contributors EMT, MJP and LMM: conception and design. All authors: acquisition of data; analysis and interpretation of data; writing, review, and/or revision of the manuscript.

  • Funding This work was supported by FIMA, Spanish Ministry of Economy and Innovation and Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional (12/02040, PI13/00806, PI14/01678, PI 14/01686, PI16/01821, RTICC RD12/0036/0040, RD01/0036/0072), PII Oncologia Torácica SEPAR y Ciber de Enfermedades Respiratorias-CIBERES–FEDER, CIBERONC and AECC Scientific Foundation (GCB14-2170).

  • Competing interests JA, EMT, MJP, RP and LMM are listed as co-inventors of a recently applied patent related to some of the results included in this manuscript.

  • Patient consent Not required.

  • Ethics approval Institutional Review Board and Ethical committees of all participating institutions: Clínica Universidad de Navarra, MD Anderson Cancer Center, Vall d’Hebron University Hospital, Hospital Germans Trias i Pujol, and Parc Taulí Universitary Hospital.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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