Oropharyngeal cancers caused by the human papillomavirus (HPV) are characterized by responding better to treatment and having a better survival rate than those not caused by the virus. Detection of the p16 protein is the most widely used test, and the one recommended by some clinical guidelines, to determine HPV causality in oropharyngeal cancer.
Now a study co-led by the Infections and Cancer group of the Bellvitge Biomedical Research Institute (IDIBELL) and the Catalan Institute of Oncology (ICO), together with the University of Birmingham, and published in The Lancet Oncology, has shown that not all p16-positive oropharyngeal cancers are caused by the HPV virus. In our area, up to 20% of p16-positive cancers do not detect DNA or RNA of the virus.
With these results, the researchers recommend performing the double test of p16 and viral DNA or RNA to determine if oropharyngeal cancer is caused by HPV. If not, a significant proportion of patients can be misclassified, which can lead to errors in its clinical management.
“When HPV infects the oropharynx epithelial cells, they overexpress the p16 protein, therefore, it is an indirect proof of viral infection with oncogenic activity. When we did not detect either viral DNA or RNA indicate that it is more probable that there have been other factors, independent of the virus, that have induced the overexpression of p16 and that it is not HPV-related cancer”, says Dr. Laia Alemany, head of the Infections and Cancer research group at IDIBELL and of the ICO and last author of the work.
Clinical implications of misclassification of oropharyngeal cancers
Because HPV-related oropharyngeal cancers have a better prognosis, several clinical trials evaluated, or are evaluating, possible de-intensification strategies in these patients.
If only p16 is considered a diagnostic biomarker of HPV causation. First, up to 20% of patients with oropharyngeal cancer can be misclassified, and most importantly, patients who do not have HPV-related oropharyngeal cancers can be deintensified. “It is very important to double-check p16 and viral DNA/RNA in all patients enrolled in de-intensification clinical trials to obtain reliable results,” the researchers say.
Geographic differences in the causation of oropharyngeal cancer
The authors collaborated with researchers from Europe and Canada to include 13 cohorts totaling nearly 8,000 oropharyngeal cancer patients from the United Kingdom, Canada, Denmark, Sweden, France, Germany, the Netherlands, Switzerland, and Spain.
The percentage of p16-positive patients in whom viral DNA/RNA is not detected varies significantly between regions. In countries where the proportion of oropharyngeal cancer caused by HPV is higher, there is less mismatch between p16 and viral DNA or RNA.
Dr. Alemany summarizes: “In those countries where the majority of oropharyngeal cancers are caused by the virus, they will have a lower percentage of discordant cases and, therefore, the double test recommendation will not be necessary. This is not the case in countries where there is a higher proportion of cancers caused by other factors such as tobacco.”
The Bellvitge Biomedical Research Institute (IDIBELL) is a biomedical research center created in 2004. It is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Institute of Health, the Catalan Institute of Oncology, the University of Barcelona and the City Council of L’Hospitalet de Llobregat.
IDIBELL is a member of the Campus of International Excellence of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centers accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the “HR Excellence in Research” program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Center of the AECC Scientific Foundation (FCAECC).