HPV-Associated Cancer Subtypes Predict Treatment Results

Human papillomavirus (HPV)-associated head and neck malignancies, known as head and neck squamous cell carcinoma (HNSCC), are on the rise in the United States. Unfortunately, little is understood about the variables that lead to these tumors, as well as what makes some cancers more aggressive and resistant to treatment than others.

Researchers from the UNC School of Medicine’s Department of Otolaryngology/Head and Neck Surgery and the Lineberger Comprehensive Cancer Center collaborated closely with researchers from Yale Cancer Center, the Yale Head and Neck Cancer Specialized Program of Research Excellence (SPORE), and the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN).

They collaborated on a recent study published in the Proceedings of the National Academy of Sciences that showed HPV+ head and neck cancers can be separated into two unique subtypes that determine how well patients respond to therapy, with one subtype being more sensitive to radiation therapy. Through the study, researchers also uncovered a new mechanism of HPV carcinogenesis, which adds to the growing attempts to customize treatment for patients with HPV+ HNSCC.

“We’re the first ones to describe these two subtypes,” said Wendell Yarbrough, MD, MMHC, FACS, the Thomas J. Dark Distinguished Professor of Otolaryngology/Head and Neck Surgery, “Using this research, we can firmly identify two groups of patients and are able to associate their tumor subtype with treatment outcomes.”

Many individuals with HPV+ HNSCC are currently treated with high-dose radiation coupled with chemotherapy. However, the negative effects, which include muscular fibrosis, difficulty swallowing, and arterial hardening, might last a lifetime. Personalized therapy may assist oncologists to make better treatment decisions for their patients; nevertheless, determining the type and degree of treatment without knowing how the patient’s tumor will respond to therapy can be problematic.

To meet this need, Yarbrough’s team members, including Travis Schrank, MD, PhD, Natalia Isaeva, PhD, and Wesley Stepp, MD, PhD, who were also co-authors on the paper, began coordinating a research cohort at UNC, grabbing publicly available data from the University of Chicago, as well as some validation data from E1308, a large national cooperative group clinical trial conducted through ECOG-ACRIN.

They next examined the tumor samples and discovered a number of groupings of co-expressed genes. Only one of these co-expressed gene sets distinguished tumors with high and low expression, and gene analysis revealed that the genes in this set were targets of a master transcription factor known as NF-kB. NF-kB is involved in inflammation and cell death and has been linked to the development of HNSCC.

Surprisingly, researchers discovered that the two unique subtypes were directly connected with patient outcomes. Tumors with low NF-kB activity had a poor prognosis, whereas tumors with high NF-kB activity had a favorable prognosis.

The subtypes identified by high or low NF-kB activity differed significantly in terms of the genes mutated in the cancers, the factors driving the mutations, the number of mutations per cancer, HPV gene expression, HPV integration, gene methylation, and infiltration of certain immune cells into the tumor.

“One of our very tenacious, intelligent residents, Wesley Stepp, who is a co-author in the paper, was really instrumental in organizing that set of patients in the UNC cohort,” said Schrank. “All of the organizations that collaborated on this research project were very willing to work with us.”

The most visible and significant distinction between the two types of malignancies was patient survival. Researchers built cellular models of each subtype in the lab to have a better grasp of why one subtype may have superior outcomes.

“Tumors with high NF-kB activity were more responsive to radiation therapy potentially contributing to improved patient survival,” said Yarbrough. “We know that there’s something about activating the NF-kB pathway that makes the tumors more sensitive to radiation therapy, which could explain how and why those patients are surviving better.”

Finally, this information could be utilized to identify patients whose therapy can be safely reduced in order to treat the tumor, reduce side effects, and improve quality of life. The discoveries may lead to the creation of novel, customized treatments that are more efficient and have fewer adverse effects now that researchers have a better knowledge of the new mechanism of HPV carcinogenesis.

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