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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2018.00589

The use of HPV16-E5, EGFR and pEGFR as prognostic biomarkers for oropharyngeal cancer patients.

  • 1Institut Català d'Oncologia, Spain
  • 2L'Hospitalet de Llobregat, Spain
  • 3Hospital de la Santa Creu i Sant Pau, Spain
  • 4Hospital del Mar, Parc de Salut Mar, Spain
  • 5Corporació Sanitària Parc Taulí, Spain
  • 6UMR5290 Maladies Infectieuses et Vecteurs Ecologie, Génétique, Evolution et Contrôle (MIVEGEC), France

Background: Anti-epithermal-growth-factor-receptor (EGFR) therapies in combination with radiotherapy are being studied on de-escalation clinical trials for HPV-related oropharyngeal cancer (OPC) patients. The HPV16-E5 oncoprotein increases recycling of activated EGFR to the cell surface, enhancing factor signal transduction. Our aim was to evaluate viral HPV16-E5 oncogene expression as well as EGFR and phosphorylated-EGFR (pEGFR), protein levels as biomarkers for clinical outcome in a retrospective cohort of OPC patients.

Methods: Formalin-fixed-paraffin-embedded OPC were collected from 1990 to 2013. OPC samples containing HPV-DNA were subject to viral E6*I mRNA detection and p16INK4a immunohistochemistry (IHC). HPV16-positive cases were evaluated for HPV16-E5 (RT-PCR) and EGFR/pEGFR (IHC). A stratified and matched random sample of HPV-negative samples was used as control and evaluated for EGFR/pEGFR. Overall survival (OS) and disease free survival (DFS) estimates were assessed for locally advanced OPC patients (stage III, IVa,b 7th edition).

Results: Among 788 OPC patient samples, 53 were double positive for HPV16-DNA/p16INK4a. HPV16-E5 expression was found in 41 of 53 samples (77.4%). EGFR expression was observed in 37.7% vs 70.8% of HPV16-positive vs HPV-negative samples, respectively; (adjusted OR= 0.15 [95%Confidence Interval=0.04-0.56). Expression of pEGFR followed an inverse pattern with 39.6% and 24.9% detection in HPV16-positive and HPV-negative samples; (adjusted OR=1.58 [95%CI=0.48-5.17]). Within HPV16-positive cases, no association between HPV16-E5/EGFR nor pEGFR was observed. With a median follow-up of 39.36 months (min=0.03-max=272.07), the combination of HPV status and EGFR or pEGFR expression were predictors of better OS (p-value<0.001, for both) and DFS (p-value<0.001 for EGFR and p-value=0.003 for pEGFR).

Conclusions: HPV16-E5 is highly expressed on HPV16-positive OPCs. Interestingly, HPV16-positive cases expressed significantly more pEGFR while HPV-negative cases expressed more EGFR. The combinations of HPV status and EGFR or pEGFR may be useful biomarkers for evaluating prognosis outcome in OPC patients.

Keywords: head and neck cancer, oropharyngeal cancer, Human papillomavirus (HPV), HPV16, EGFR, HPV16-E5

Received: 29 Aug 2018; Accepted: 22 Nov 2018.

Edited by:

Jesper G. Eriksen, Department of Oncology, Odense University Hospital, Denmark

Reviewed by:

Orlando Guntinas-Lichius, Universitätsklinikum Jena, Germany
Ruveyda Dok, KU Leuven, Belgium  

Copyright: © 2018 Taberna, Torres, Alejo, Mena, Tous, Marquez, Pavón, León, Garcia, Güix, Hijano, Bonfill, Aguilà, Lozano, Mesia, Alemany and Bravo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Miren Taberna, Institut Català d'Oncologia, Barcelona, Spain,