AUTHOR=Taberna Miren , Torres Montserrat , Alejo María , Mena Marisa , Tous Sara , Marquez Sandra , Pavón Miquel A. , León Xavier , García Jacinto , Guix Marta , Hijano Rafael , Bonfill Teresa , Aguilà Antón , Lozano Alicia , Mesía Ricard , Alemany Laia , Bravo Ignacio G. 

TITLE=The Use of HPV16-E5, EGFR, and pEGFR as Prognostic Biomarkers for Oropharyngeal Cancer Patients

JOURNAL=Frontiers in Oncology

VOLUME=8

YEAR=2018

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2018.00589

DOI=10.3389/fonc.2018.00589

ISSN=2234-943X

ABSTRACT=<p><bold>Background:</bold> Anti-epidermal-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-<italic>E5</italic> oncogene expression as well as EGFR and phosphorylated-EGFR (pEGFR), protein levels as biomarkers for clinical outcome in a retrospective cohort of OPC patients.</p><p><bold>Methods:</bold> Formalin-fixed-paraffin-embedded OPCs were collected from 1990 to 2013. OPC samples containing HPV-DNA were subject to viral <italic>E6</italic><sup>*</sup><italic>I</italic> mRNA detection and p16<sup>INK4a</sup> immunohistochemistry (IHC). HPV16-positive cases were evaluated for HPV16-<italic>E5</italic> (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).</p><p><bold>Results:</bold> Among 788 OPC patient samples, 53 were double positive for HPV16-DNA/p16<sup>INK4a</sup>. HPV16-<italic>E5</italic> expression was found in 41 of 53 samples (77.4%). EGFR expression was observed in 37.7 <italic>vs</italic> 70.8% of HPV16-positive <italic>vs</italic> HPV-negative samples, respectively; (adjusted OR = 0.15) 5% CI = 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-<italic>E5</italic>/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 (<italic>p</italic> &lt; 0.001, for both) and DFS (<italic>p</italic> &lt; 0.001 for EGFR and <italic>p</italic> = 0.003 for pEGFR).</p><p><bold>Conclusions:</bold> HPV16-<italic>E5</italic> 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.</p>