p16INK4a (p16) immunostaining is the most widely implemented technique in clinical settings for determining HPV causation and HPV-related prognosis biomarker of oropharyngeal cancer (OPC). A subset of p16+ OPC are HPV-; and their prognosis is still unclear. The aim of this study is to clearly define the proportion, determinants and prognosis of OPC patients who are p16+/HPV-.
We established an international consortium comprising 13 cohorts of OPC patients with data on p16, HPV, demographics, tobacco/alcohol use and clinical data. A centralized individual patient data reanalysis was performed. Multivariate models were used to evaluate factors associated with HPV status as defined by different HPV-assessment methods. Proportional-hazards models were used to compare the risk of death (OS) among HPV-related and un-related OPC.
In total 7702 patients from 9 different countries were included. The percentage of positive cases was 49.7%, 47.9% and 44.3% for p16+, HPV+ and p16+/HPV+, respectively. Among p16+ cases, 10.9% were HPV-. This proportion differed significantly by cohorts and geographic areas (p-value<0.001) and was lowest in the highest prevalence areas (Table). Compared to p16-/HPV- tumors, p16+/HPV+was the biomarker with strongest prognostic value (aHR 0.28, 95%CI 0.25-0.31), followed by p16+/HPV- (aHR=0.65, 95%CI 0.56-0.76), and p16-/HPV+ (HR=0.72, 95%CI 0.60-0.86). Disease-free/OPC-specific survival analyses will be presented at the congress. p16+/HPV- by region and cohort from the EPIC-OPC study *p16+/HPV- percent among p16 tested.
Region/Cohort Total N P16+ N P16+/HPV- N (%)* North America 186 135 2 1.5 Canada-Toronto 186 135 2 Denmark-Copenhagen 2169 1324 123 UK-Birmingham 816 499 58 UK-Liverpool 252 152 12 UK-Belfast 232 95 11 The Netherlands-Amsterdam/Rotterdam 1203 388 48 Germany-Giessen 704 235 40 Germany-Cologne 205 111 17 Germany-Kiel 126 58 11 Sweden-Stockholm 539 375 24 Switzerland-Zurich 134 83 7 France-Paris 275 275 275 Spain-Barcelona 861 95 28
p16+/HPV+ tumors showed the highest OS magnitude of association compared with other biomarkers combinations. Using p16 immunostaining alone, 11% OPC patients would be incorrectly classified as HPV-related OPC according to TNM-8 staging, and with risk of misclassification for de-escalation in clinical trials, particularly in regions with lower attributable fractions of HPV.
Catalan Institute of Oncology.
Has not received any funding.
All authors have declared no conflicts of interest.