Discordant Biomarkers Foretell Prognosis in Oropharyngeal Cancer

Mismatch between the p16 protein and human papillomavirus (HPV) biomarkers can help determine prognosis in patients with oropharyngeal cancer, European researchers reported.

Specifically, oropharyngeal cancer patients with discordance between the p16 (p16^INK4a ) and HPV biomarker had significantly worse disease-free survival (DFS) and overall survival (OS) than double-positive patients, though significantly better survival than double-negative patients, according to Hisham Mehanna, MBChB, PhD, of the Institute of Cancer and Genomics Sciences at the University of Birmingham in England, and colleagues, writing in Lancet Oncology.

Five-year DFS and OS rates in their multinational, individual patient data analysis involving almost 8,000 patients were as follows:

• Double-positive (p16+/HPV+): 84.3% and 81.1%, respectively
• Discordant (p16-/HPV+): 71.1% and 53.2%
• Discordant (p16+/HPV-): 67.9% and 54.7%
• Double-negative (p16-/HPV-): 60.8% and 40.4%

“Our findings indicate that classification of patients with oropharyngeal cancer based on p16-positive immunohistochemistry alone is inadequate in a trial setting, and is likely to be insufficient in routine clinical practice, both for predicting prognosis and when selecting treatment,” the authors wrote.

They explained that the incidence of oropharyngeal cancer globally has been on the rise since 2000, mostly due to an increase in HPV-mediated disease. Overexpression of the protein p16 on immunohistochemistry is widely used as a surrogate for determining HPV mediation because of the cost and difficulty in implementing HPV DNA and RNA testing.

However, a number of patients have discordant biomarker status, and results concerning the prognostic significance of this discordant group have been contradictory, they noted.

“To the best of our knowledge, this multicenter, international study represents by far the largest effort to identify the contribution of p16 and HPV biomarkers in determining prognosis in patients with oropharyngeal cancer,” Mehanna and colleagues said. “In an era where oropharyngeal cancer has been shown to have at least two subtypes with very different prognoses, this information is crucial to accurately classify this population of patients, and thereby aid appropriate patient selection for de-escalation or escalation of treatment.”

This study included individual patient data from 13 cohorts of patients (n=7,895) with oropharyngeal cancer from several countries, including the U.K., Canada, Denmark, Germany, The Netherlands, and Switzerland.

Of 7,654 patients (nearly three-fourths male) eligible for p16 and HPV analysis, 46.5% were double-negative, 44.3% double-positive, 3.8% were p16-/HPV+, and 5.4% were p16+/HPV-. Among the 3,805 p16-positive patients, 10.9% did not show presence of HPV, while of the 3,849 p16-negative patients, 7.5% showed presence of HPV.

Compared with double-positive patients, the 5-year adjusted hazard ratios (HRs) for DFS and OS, respectively, demonstrated significantly worse survival outcomes for all other groups:

• Discordant (p16-/HPV+): HR 2.36 (95% CI 1.87-3.97) and HR 3.15 (95% CI 2.50-3.97)
• Discordant (p16+/HPV-): HR 1.92 (95% CI 1.42-2.60) and 2.69 (95% CI 2.21-3.29)
• Double-negative (p16-/HPV-): HR 3.27 (95% CI 2.84-3.76) and 4.05 (95% CI 3.59-4.58)

Mehanna’s group found that the prognostic patterns described above were consistent regardless of the region of Europe, the anatomical subsite, and when analyzing different HPV testing methods. However, they also noted that the prognosis between the different p16 and HPV subgroups differed significantly by smoking status.

OS in p16+/HPV- never-smokers was comparable to that of double-positive never-smokers. However, double-negative ever-smokers had a much worse OS than double-positive ever-smokers (adjusted HR 2.94, 95% CI 2.37-3.64), though OS did not differ from p16-/HPV+ ever-smokers or double-negative ever-smokers.

Study limitations included its retrospective design and the use of a variety of tests for p16 and HPV based on institutional preference, although the authors argued that the latter point “could also be considered a strength of this study, because it replicates the real-world setting, in which different institutions would use different p16 and HPV assays.”