Evaluation of p16(INK4a) expression as a single marker to select patients with HPV-driven oropharyngeal cancers for treatment de-escalation

BACKGROUND: A remarkably better prognosis is associated with oropharyngeal squamous cell carcinomas (OPSCC) driven by human papillomaviruses (HPV) compared with HPV-negative OPSCC. Consequently, de-escalation of standard treatment has been suggested. Due to modest specificity rates, debates are ongoing, whether p16(INK4a), a surrogate marker for HPV-driven OPSCC, is sufficient to correctly identify those tumours and avoid substantial HPV misattribution and thus undertreatment of patients by de-escalation. Robust data estimating the proportion of potentially undertreated patients are missing. METHODS: We assessed a large-scale cohort of consecutively included OPSCC diagnosed between 2000 and 2017 for HPV–DNA, HPV genotypes, p16(INK4a) expression and multiple tumour- and patient-related risk factors, and investigated their impact on patients’ survival in comprehensive uni- and multivariate analyses. RESULTS: Aetiological relevance of HPV (p16(INK4a)- and high-risk HPV–DNA-positivity) was detected in 27.1% (n = 192) of OPSCC, with HPV(16) being the most abundant HPV type (94.6%). In 5.5% patients (n = 39), p16(INK4a) overexpression but no HPV–DNA was detected. Principal component and survival analyses revealed that 60.6% of these p16(INK4a)-positive OPSCC lacking HPV–DNA did not resemble HPV(16)-driven but HPV-negative OPSCC regarding risk-factor profile and overall survival. Notably, this group represented 10.6% of all p16(INK4a)-overexpressing OPSCC. CONCLUSIONS: p16(INK4a) as a single marker appears insufficient to indicate OPSCC patients suitable for treatment de-escalation.