Evaluation of p16INK4a expression as a single marker to select patients with HPV-driven oropharyngeal cancers for treatment de-escalation

Steffen Wagner,Claus Wittekindt,Magnus Von Knebel Doeberitz,Theresa Obermueller,Elena-Sophie Prigge,Jens Peter Klussmann,Jörn Pons-Kühnemann,Ayman Bushnak,Henrike Reder,Gregor Wolf,Shachi Jenny Sharma,Nora Wuerdemann,Thomas Dreyer,Stefan Gattenlöhner

doi:10.1038/s41416-020-0964-x

Abstract

BackgroundA 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 p16INK4a, 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.MethodsWe assessed a large-scale cohort of consecutively included OPSCC diagnosed between 2000 and 2017 for HPV–DNA, HPV genotypes, p16INK4a expression and multiple tumour- and patient-related risk factors, and investigated their impact on patients’ survival in comprehensive uni- and multivariate analyses.ResultsAetiological relevance of HPV (p16INK4a- and high-risk HPV–DNA-positivity) was detected in 27.1% (n = 192) of OPSCC, with HPV16 being the most abundant HPV type (94.6%). In 5.5% patients (n = 39), p16INK4a overexpression but no HPV–DNA was detected. Principal component and survival analyses revealed that 60.6% of these p16INK4a-positive OPSCC lacking HPV–DNA did not resemble HPV16-driven but HPV-negative OPSCC regarding risk-factor profile and overall survival. Notably, this group represented 10.6% of all p16INK4a-overexpressing OPSCC.Conclusionsp16INK4a as a single marker appears insufficient to indicate OPSCC patients suitable for treatment de-escalation.

Highlights

A remarkably better prognosis is associated with oropharyngeal squamous cell carcinomas (OPSCC) driven by human papillomaviruses (HPV) compared with HPV-negative OPSCC
DNA from non-HR–HPV types was detected in 5 (0.7%) OPSCC only, two of them corresponding to the low-risk (LR) types 6 and 11 (Table 2)
HPV16 was the most frequent among all HPV types, identified as the exclusive type in 91.2% of p16INK4a only is inadequate for patient selection

Summary

Introduction

A remarkably better prognosis is associated with oropharyngeal squamous cell carcinomas (OPSCC) driven by human papillomaviruses (HPV) compared with HPV-negative OPSCC. Principal component and survival analyses revealed that 60.6% of these p16INK4a-positive OPSCC lacking HPV–DNA did not resemble HPV16-driven but HPV-negative OPSCC regarding risk-factor profile and overall survival This group represented 10.6% of all p16INK4a-overexpressing OPSCC. Persistent infections with high-risk (HR) human papillomavirus (HPV) types are causative for about 31% of oropharyngeal squamous cell carcinomas (OPSCC).[1] Importantly, the incidence of HPV-driven OPSCC has been rising in several countries worldwide,[1,2,3] albeit heterogeneity exists regarding anatomic subsite, geography and sex.[4] Patients with HPV-driven OPSCC are reported to have a different risk profile (younger age, reduced tobacco/alcohol consumption) in comparison with HPV-negative OPSCC.[5,6] Likewise, patients’ survival is remarkably better, most patients present with smaller primary tumours, but more advanced cervical lymph node metastasis status compared with HPV-negative OPSCC patients.[5] In view of the superior survival, several clinical phase I–III trials are currently investigating the benefits of de-escalating treatment for this patient group to spare them treatment-associated morbidity.[7,8,9,10,11].

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