Patients with HPV associated (HPV+ve) head and neck squamous cell carcinoma (HNSCC), particularly oropharyngeal cancer, show better treatment response, higher survival rates, and lower risks of recurrence as compared to HPV-ve HNSCC patients. Despite increased sensitivity to treatment modality, HPV+ve HNSCC patients are subjected to the same intensive anti-cancer therapy as HPV-ve HNSCC patients and thus subjecting them to unwarranted long-term toxicity. To identify predictive biomarkers for risk-stratification, we have analyzed the mutational spectrum, and the evidence suggests that gain-of-function mutations in the NRF2 pathway are highly prevalent in HPV-ve HNSCC. At the same time, it is rare in HPV+ve HNSCC tumors. We have reviewed the importance of gain-of-NRF2 function and loss of p53 in the prognosis of HNSCC patients and discussed a predictive scoring system using a combination of HPV status (p16), NRF2 pathway and p53 to stratify HPV+ve HNSCC into good versus poor responders, which could immensely help in guiding future de-escalation treatment approaches in patients with HPV+ve HNSCC.
Keywords: Chemoradioresistance; HPV; NRF2; Oropharyngeal cancer; Therapeutic de-escalation; p53.
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