Five Genetic Subgroups Revealed in Head and Neck Tumor Analysis

Ezra E.W. Cohen, MD

Associate Professor, Section of Hematology/Oncology, Department of Medicine, Co-Director, Head and Neck Cancer Program, Director, Hematology/Oncology Fellowship Program, University of Chicago Medical Center, Chicago, IL

Oncologists who treat patients with head and neck cancer are aware that those whose disease has been caused by human papillomavirus (HPV) have significantly better outcomes than those whose disease is caused by other factors such as smoking. However, new research suggests that there may be five distinct subgroups in which specific genetic profiles may be utilized to guide treatment decisions in patients.

“Currently, we treat all patients with head and neck cancer in essentially the same way,” said Ezra E. W. Cohen, MD, co-director of the Head and Neck Cancer Program at the University of Chicago Medical Center. “But we do know that the prognosis for patients who are HPV-positive is much better.”

To determine whether patients’ genetic profiles differed, Cohen and his colleagues at the University of Chicago, led by researcher Tanguy Seiwert, MD, took approximately 130 tumor samples from patients with stage IV squamous cell carcinoma of the head and neck and performed gene expression (mRNA) analysis.

The samples were gathered before patients received therapy, and all of the participants subsequently were treated with a 5-fluorouracil, hydroxyurea, and concurrent radiation (FHX)-based regimen. This way, the researchers could determine the outcome as a function of gene expression in the groups identified through the analysis, since patients received the same treatment across all the subgroups eventually identified. Cohen said that patients were enrolled regardless of whether they were HPV-positive or HPV-negative.

Based on these findings, the University of Chicago team was able to classify head and neck cancer into five different subgroups: hypoxic, basal, classical, HPV-associated type A, and HPV-associated type B.

The first three types⎯hypoxic, basal, and classical⎯are not associated with HPV. Cohen said hypoxia occurs in about one out of five head and neck cancer cases, and it can lead to increased resistance to therapy, supporting the notion that HPV-negative cancers are associated with poorer prognoses. The basal type is associated with epithelial cell differentiation and involves the RAB3 pathway, while the classical type can involve cell cycle disruptions. Cohen said that in these subgroups, the survival was worse, although the exact reasoning behind the poorer prognosis is not yet known.

“Biologically, these tumors are more resistant to standard therapy,” Cohen said. “We do not know exactly why that is.”

Cohen noted that while the prognosis is better in HPV-positive cases of head and neck cancer, better outcomes were observed in tumors that were classified as HPV-associated type A compared with type B. In type A, researchers found alterations associated with immune response, and the analyses revealed some potential targets for which treatments have been or are currently being developed, including the programmed death-1 (PD-1) pathway.

Type B had some similarities to the basal type of head and neck cancer, Cohen said.

As far as potential targets, Cohen said that about 20% of patients with HPV-related head and neck cancer had mutations in PIK3CA and 30% overall had an amplification of PIK3CA. Cohen said that information about the biology of these tumors hopefully would help researchers understand why the prognosis is worse in type B than in type A.

The research has been submitted for publication, and Cohen said that more work needs to be done to determine the clinical significance of these findings. Additionally, better and more cost-effective methods of screening are required to separate larger patient populations into these subgroups.

“It would be far too expensive to do mRNA analysis on every single head and neck cancer patient,” Cohen said. “If we know which changes are most pronounced within those five subgroups, then perhaps there is a better method of identifying them and classifying patients so that they can receive the appropriate treatment.”