Human papillomavirus (HPV)–positive head and neck squamous cell carcinomas can be divided into two distinct subtypes that may help determine how well patients will respond to therapy, according to a novel study published by Schrank et al in PNAS. The findings also identified a new mechanism of HPV carcinogenesis that could enhance efforts to personalize treatments for patients with HPV-positive head and neck squamous cell carcinoma.
Background
Cases of HPV-positive head and neck squamous cell carcinoma, have been rapidly increasing throughout the United States. However, the factors contributing to these tumors and what makes some tumors more aggressive and treatment-resistant than others are not well understood.
Currently, many patients with HPV-positive head and neck squamous cell carcinoma are treated with high doses of radiation therapy combined with chemotherapy. However, the side effects—which include muscle fibrosis, swallowing difficulties, and atherosclerosis—can last a lifetime. Personalized therapy may allow oncologists to make better treatment choices for their patients, but it can be difficult for physicians to determine the type and intensity of treatment without knowing how the patients’ tumors will respond to therapy.
Study Methods and Results
In the new study, the researchers analyzed the tumor samples of 104 patients with HPV-positive head and neck squamous cell carcinoma as well as data from the University of Chicago and the E1308 clinical trial in order to determine the factors contributing to patients’ response to radiation therapy.
The researchers then identified several groups of coexpressed genes—only one of which separated tumors with high and low expression. They found that the genes in this set represented targets of a master transcription factor called NF-kB, a protein complex that has been shown to play an important role in inflammation and cell death and has been associated with the carcinogenesis of head and neck squamous cell carcinoma.
Additionally, the researchers discovered that the two distinct subtypes of the tumors directly correlated with patient outcomes. Tumors with low NF-kB activity were associated with worse prognoses, whereas tumors with high NF-kB activity were associated with a better prognoses.
The subtypes identified by high or low NF-kB activity also presented with significant differences in their characteristics—including the genes that were mutated in the cancers, 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 tumors.
Patient survival was the most notable distinction between the two subtypes of tumors. To get a better understanding of why one subtype may have had better outcomes, the researchers constructed cellular models for each subtype.
“Tumors with high NF-kB activity were more responsive to radiation therapy, potentially contributing to improved patient survival,” highlighted co–senior study author Wendell Yarbrough, MD, MMHC, FACS, the Thomas J. Dark Distinguished Professor of Otolaryngology/Head and Neck Surgery at the University of North Carolina at Chapel Hill School of Medicine. “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,” he added.
Conclusions
“We're the first ones to describe these two subtypes,” explained Dr. Yarbrough. “Using this research, we can firmly identify two groups of patients and are able to associate their tumor subtypes with treatment outcomes,” he underscored.
The results of the new study could be used to identify patients whose therapy can be safely de-intensified in order to treat their tumors, lessen their side effects, and enhance their quality of life. The researchers hope that with a greater understanding of the new mechanisms of HPV carcinogenesis, their findings could lead to the development of novel personalized therapeutics that are more efficient and have fewer side effects than current treatment options.
Disclosure: For full disclosures of the study authors, visit pnas.org.
