# Nuclear factor E2 p45-related factor (NRF2) and peroxiredoxin 6 tissular expression as prognostic biomarkers for advanced HPV-negative squamous cell carcinoma of the oropharynx

## TL;DR

This study shows that high levels of NRF2 and peroxiredoxin 6 in oropharyngeal tumors are linked to worse survival outcomes, especially in HPV-negative patients.

## Contribution

The study identifies NRF2 and peroxiredoxin 6 as novel prognostic biomarkers for HPV-negative oropharyngeal squamous cell carcinoma.

## Key findings

- NRF2 and peroxiredoxin 6 are overexpressed in tumor tissue compared to healthy tissue.
- High expression of peroxiredoxin 6 is significantly associated with worse progression-free and overall survival.
- Combined high expression of NRF2 and peroxiredoxin 6 is linked to the worst survival outcomes.

## Abstract

•NRF2 and peroxiredoxin 6 are overexpressed in tumor tissue compared to healthy tissue prior to any treatment, suggesting their involvement in therapy resistance.•High tumoral expression of NRF2 or peroxiredoxin 6 are negative prognostic factors on survival outcomes in non-HPV-induced oropharyngeal SCC patient.•Associating peroxiredoxin 6 and NRF2 expression improves patient survival prediction.

NRF2 and peroxiredoxin 6 are overexpressed in tumor tissue compared to healthy tissue prior to any treatment, suggesting their involvement in therapy resistance.

High tumoral expression of NRF2 or peroxiredoxin 6 are negative prognostic factors on survival outcomes in non-HPV-induced oropharyngeal SCC patient.

Associating peroxiredoxin 6 and NRF2 expression improves patient survival prediction.

Non-HPV-induced squamous cell carcinomas (SCC) of the oropharynx have a poorer prognosis than HPV-induced cancers because they are more radio- and chemoresistant. Currently, no predictive biomarker exists for survival outcome in this type of tumor. NRF2 is a nuclear transcription factor that regulates the expression of cytoprotective genes, and peroxiredoxin 6 is one of the proteins regulated by NRF2. Both are potentially involved in the resistance to treatments as they play a central role in the response to oxidative stress.

In a retrospective cohort study of 53 patients with advanced HPV-negative squamous cell carcinomas of the oropharynx, we studied the correlation between clinical characteristics, response to treatment (surgery + radiotherapy), patient survival, and the expression of NRF2 and peroxiredoxin 6 in pre-treatment tumor biopsies. We prepared Tissue Micro Arrays (TMA) before performing immunohistochemistry analyses.

For a given patient, prior to any treatment, NRF2 and peroxiredoxin 6 are overexpressed in tumor tissue compared with healthy tissue. Moreover, patients with high NRF2 expression tended to have poorer progression-free survival (p = 0,09). Patients with high expression of peroxiredoxin 6 had significantly worse progression-free survival and overall survival (p = 0.015 and p < 0.01, respectively). The combination of high NRF2 and peroxiredoxin 6 expression was associated with even worse survival outcomes (p < 0.01and p = 0.01, respectively).

Elevated expression levels of peroxiredoxin 6, either alone or in combination with NRF2, are poor prognostic indicators for patient survival.