Natalia Issaeva, Barbara Burtness and Wendell G. Yarbrough*
The incidence of HPV-associated (HPV+) Head and Neck Squamous Cell Carcinomas (HNSCC) has dramatically increased over the last 2 decades and continues to rise. These tumors are distinct from tobacco-associated HNSCC and have improved response to therapy and survival. Despite molecular, demographic and response differences between HPV+ and HPV-negative tumors, they are each treated with aggressive multi-modality therapy that can result in lifelong morbidity. To minimize long term morbidity, there are ongoing efforts to de-escalate therapy for HPV + HNSCC, but tools for selection of appropriate low risk patients has been limited without available molecular markers of tumor response. In addition, more targeted and less morbid therapies for HPV+ are not currently available. Recently, inactivating defects of the TNF Receptor-Associated Factor 3 (TRAF3) and cylindromatosis (CYLD) genes were identified in approximately 30% of HPV+ HNSCC and associated with improved survival, possibly accounting for the entire survival advantage of HPV association in HNSCC. In addition, gene expression analysis revealed that loss of TRAF3/CYLD was associated with increased NF-kB and decreased type I interferon signaling, suggesting that reversing these changes in signaling could offer new treatment strategies. Here we review the potential to use TRAF3/CYLD status of HPV+ HNSCC as a marker of selection for therapeutic de-escalation, or as an indication of new therapies that could be used to target this subset of tumors.
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