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 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) 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.
Highlights
Chronic infection by oncogenic Human Papillomaviruses (HPVs) is the principal cause of the increasing incidence rates of oropharyngeal carcinoma (OPC) [1].Viral transformation concurs with a lower mutational burden, resulting in better prognosis for patients with HPV-related OPCs [2]
The demographic and clinical characteristics associated with HPV16-E5 expression, Epidermal Growth Factor Receptor (EGFR) and pEGFR levels, stratified by HPV status, as well as the crude Odds Ratio (OR) measures of association are shown in Supplementary Table S2
Since HPV16 integration often concurs with E5 ablation, all samples that tested negative for the presence of HPV16-E5 mRNA (12/53) were further tested for HPV16-E5 DNA, and 58.3% (7/12) were positive
Summary
Chronic infection by oncogenic Human Papillomaviruses (HPVs) is the principal cause of the increasing incidence rates of oropharyngeal carcinoma (OPC) [1].Viral transformation concurs with a lower mutational burden, resulting in better prognosis for patients with HPV-related OPCs [2]. Chronic infection by oncogenic Human Papillomaviruses (HPVs) is the principal cause of the increasing incidence rates of oropharyngeal carcinoma (OPC) [1]. Therapies targeting the Epidermal Growth Factor Receptor (EGFR) have been proposed as de-escalation strategies in HPV-related OPC patients, as an alternative to cisplatin when given concurrently with radiation therapy, attempting to reduce cisplatin side-effects [4, 5]. 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. 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
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