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This work was supported by grants from Ayudas Merck Serono Investigacion_Salud 2000, Instituto de Salud Carlos III-ISCIII (Spanish Government) cofunded by FEDER funds/European Regional Development Fund (ERDF)-a way to build Europe (References: PI1102096, PI1401918, PI1500500, PI1501205, RD12/0036/0056, CIBERESP CB06/02/0073, CIBERONC CB16/12/00401). With the support of the Secretariat for Universities and Research of the Department of Business and Knowledge of the Government of Catalonia. Grants to support the activities of research groups (SGR 2014-2017: 2014SGR756 and 2014SGR1077; 2017-2019: 2017SGR1085). Beca de recerca clinica 2016 de l'Academia de Ciencies Mediques de Catalunya i Balears, Department of Health of the Generalitat de Catalunya (PERIS-2016-2020, SLT002/16/00404). Asociacion Espanola Contra el Cancer (personal grant to LA), Rio Hortega-SEOM (ISCIII-Spanish Society of Medical Oncology) (personal grant to MT), and from Sanofi Pasteur MSD and Merck and Co., Inc. None of the funders had any role in the data collection, analysis, interpretation of the results, article writing, and decision to publish.

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

Publicated to:Frontiers In Oncology. 8 (DEC): 589- - 2018-12-11 8(DEC), DOI: 10.3389/fonc.2018.00589

Authors: Taberna, M; Torres, M; Alejo, M; Mena, M; Tous, S; Marquez, S; Pavon, MA; Leon, X; Garcia, J; Guix, M; Hijano, R; Bonfill, T; Aguila, A; Lozano, A; Mesia, R; Alemany, L; Bravo, IG

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Abstract

Background: 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-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 OPCs were collected from 1990 to 2013. OPC samples containing HPV-DNA were subject to viral E6* I mRNA detection and p16(INK4a) 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/p(16INK4a). 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) 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-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 < 0.001, for both) and DFS (p < 0.001 for EGFR and p = 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.

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