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Top Line: What is the prognosis of oropharyngeal cancers that have discordant p16 and HPV positivity

The Study: p16 expression is often used as a surrogate marker of HPV-mediated oropharyngeal carcinoma. However, some tumors may be p16 positive but HPV negative or vice versa. While this would mainly have prognostic implications, there could be important therapeutic implications as treatment de-intensification evolves for HPV-mediated disease. This study assembled data from 7654 patients from 13 international cohorts to assess discordance between p16 testing and HPV testing for oropharyngeal cancer. The majority of patients were either double positive (p16+/HPV+, 44.3%) or double negative (46.5%). Overall, 5.4% of patients were p16+ but HPV-, and 3.8% were p16- but HPV+. Put another way, 10.9% of p16+ patients were HPV-, and 7.5% of p16- patients were HPV+. HPV testing was a mix of DNA or RNA PCR or DNA or RNA in-situ hybridization. DIscordance was more common in oropharynx subsites outside the tonsil and base of tongue (29.7% v 9%). Patients with discordant p16/HPV had OS and DFS outcomes that fell between those of p16+/HPV+ and p16-/HPV- disease. At 5 years, OS was 81.8% for p16+/HPV+, 54.7% for p16+/HPV-, 53.2% for p16-/HPV+, and 40.4% for p16-/HPV-. Likewise, 5-year DFS was 84.3%, 67.9%, 71.1%, and 60.8%. Smoking continued to play an important prognostic role with discordant never smokers having similar prognosis to p16+/HPV+ patients. However, discordant smokers had worse prognosis than p16+/HPV+ smokers. So why the discordance? The authors hypothesize that p16+/HPV- never smokers may still have HPV-mediated disease but with lower copy numbers that aren’t detectable. p16+/HPV- smokers may represent a subset of tumors driven by non-HPV genomic alterations.

TBL: Prognosis for p16/HPV discordant oropharyngeal cancer falls between that of p16+/HPV+ and p16-/HPV- disease, and it is highly influenced by smoking history. | Mehanna, Lancet Oncol 2023