NRF2, p53, and p16: Predictive biomarkers to stratify human papillomavirus associated head and neck cancer patients for de-escalation of cancer therapy

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.