Human papillomavirus (HPV) has been linked to a significant increase in cancers of the throat and tonsils over the past few decades; this is projected to become the most common form of head and neck cancer by 2030. But a major limitation to reducing treatment intensity is the inability to correctly identify the patients whose HPV-related cancers will be the most responsive to treatment. In this new study, researchers identified a novel subclass of HPV+ head and neck squamous cell carcinoma (HNSCC) and demonstrated that treatment could be tailored by tumor type.

The study was published in Proceedings of the National Academy of Sciences (PNAS) on July 31. This research was made possible through the Yale Head and Neck SPORE program and the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN).

"Our findings reveal that there are two fundamentally different subtypes of HPV+ HNSCC, each with unique characteristics and treatment responses,” said Barbara Burtness, MD, co-author of the study and chief translational research officer at Yale Cancer Center. “This discovery opens new opportunities for treatment personalization, as we can now better understand the distinct requirements for tumor development in each subclass,” said Burtness, who also is Anthony N. Brady Professor of Medicine at Yale School of Medicine. For ECOG-ACRIN, Burtness chairs the Head and Neck Cancer Committee and the Task Force on Advancement for Women.

In this study, researchers analyzed data from 104 HPV+ HNSCC tumors and two publicly available sources to identify gene expression patterns (modules) that could consistently classify different tumor types. Among 22 modules, researchers say one emerged that effectively categorized HPV+ HNSCC tumors based on a distinct gene expression pattern. Among patients treated on the ECOG-ACRIN Cancer Research Group trial E1308, which de-intensified treatment for HPV+ head and neck cancers, the NFKB classifier accurately predicted a favorable outcome, even with reduced dose radiation.

The critical distinction between the two classes of HPV-associated head and neck cancers was in the activation of NF-κB signaling, a crucial molecular pathway associated with cellular growth, the formation of new blood vessels, and increased protection against cell death. Patients within this subclass showed improved clinical outcomes, and their tumors demonstrated increased sensitivity to radiation therapy.

“This research represents a breakthrough in understanding HPV-associated head and neck cancer,” said Burtness. “Currently, aggressive combination therapy is used to treat HPV+ HNSCC, but this new data shows that patient responses could vary significantly depending on the specific molecular features of their tumor. With the identification of distinct tumor subclasses, we may be able to tailor treatments to individual patients, potentially reducing their suffering from treatment, while also helping with therapeutic decisions.”

Travis Schrank, MD, PhD, at the University of North Carolina was the study’s first author. Karen Anderson, PhD, from Yale School of Medicine, joined Burtness as a co-author.