Underlying Biology of HPV-Positive and -Negative HNSCC
Transcript:Ezra Cohen, MD: Hello, and thank you for joining us today for this OncLive Peer Exchange® panel discussion on “A New Era for Treatment of Advanced Head and Neck Cancers.” The epidemiology of squamous cell carcinoma of the head and neck, or HNSCC, which are historically tobacco- and alcohol-associated cancers, has shifted in recent years to reflect an increase in human papillomavirus-driven tumors, or HPV. Next-generation sequencing efforts are beginning to shed light on the hidden complexities of these tumors, leading to the identification of multiple molecular subtypes. As key differences between tumors with and without HPV infection are beginning to emerge, the challenge is to find ways to use this information to personalize treatment for individual patients. This OncLive Peer Exchange® panel discussion will focus on how patients are treated in 2016, as the first FDA approval of checkpoint inhibitors for advanced head and neck cancers leads us into a new era.
I’m Dr. Ezra Cohen, a professor of medicine in the Division of Hematology-Oncology and Department of Medicine, associate director for Translational Science, and co-leader of the Solid Tumor Therapeutics Program at the University of California San Diego Moores Cancer Center. Participating today on our distinguished panel are: Dr. Viktor Grünwald, professor of hematology and oncology in the Department of Hematology Oncology at Hannover Medical School in Hannover, Germany; Dr. Kevin Harrington, professor in biologic cancer therapies at the Institute of Cancer Research and the Roy Marsden National Health Service Foundation in London; and Dr. Tanguy Seiwert, associate program director for Head and Neck Cancer at the University of Chicago Medical Center in Chicago, Illinois. Thank you so much for joining us today. Let’s begin.
Let’s first talk about the biology of head and neck squamous cell carcinoma, what’s known about the underlying biology with respect to carcinogenesis, and the etiology of this disease. Kevin, maybe you can start us off.
Kevin Harrington, MD, PhD: So, we know that, traditionally, head and neck cancer is associated with people who have had a relatively heavy tobacco consumption and is often also associated with alcohol consumption. And we’re beginning to learn from the TCGA (The Cancer Genome Atlas) analysis that these tumors are associated with a relatively heavy mutational load, indicating that carcinogens are playing a key role in driving these malignancies. We know that 84% or more of head and neck cancers will have abnormalities in their p53 signaling pathways, and this seems to be one of the major driving events. And we know increasingly that there are subtypes of tumors that have different mutational loads. In addition to that, we know that there are newer forms of cancer emerging, including virally-induced malignancies.
Ezra Cohen, MD: Viktor, do you want to comment on that at all?
Viktor Grünwald, MD: Yes. I think the HPV is one of the major players nowadays, and it certainly had an impact on how we approach our patients. It has a major impact for oropharyngeal cancer, for instance, and certainly has different prognostic aspects that vary depending on the location of the occurrence of the cancer and being HPV-positive or -negative.
Ezra Cohen, MD: We really are beginning to see head and neck cancer split into two major groups: HPV-associated (or pharynx) cancers and HPV-negative tobacco-induced. But, Tanguy, there’s still a fair bit of heterogeneity, even when separating for those two groups. Talk to us a little bit about that.
Tanguy Y. Seiwert, MD: I think, just in general, we are seeing a shift in the fraction of HPV-positive versus HPV-negative patients, especially in the United States and also in Europe. The fraction of HPV-positive tumors has increased consistently, and actually, some people call it an “epidemic” of these tumors. At the same time, there still is a fair amount of these HPV-negative tumors. And we know clinically that they’re actually quite distinct. We realize that the HPV-positive tumors tend to have a better prognosis, and they have higher cure rates. But even with other modalities, in general, with radiation, with chemotherapy, and probably even with surgery, they tend to do somewhat better. And I think we’ll also talk about immunotherapy in a later segment.
When we look at them biologically, they’re actually also distinct. They have different genetic fingerprints. And, as was mentioned already, we see TP53, or p53, aberrations primarily, almost exclusively, in the HPV-negative tumors. While in the HPV-positive tumors, we obviously have aberrations of the cell cycles that come from the HPV virus directly, E6/E7. Cyclin D1 amplification is one that preferentially occurs in HPV-negative tumors. And then we see PI3K aberrations across the board in probably all tumors. So, I think that’s a quick summary, but the fingerprint is different between these entities, which may model or show why they’re all so different clinically.
Ezra Cohen, MD: So, Tanguy, even within these large groups of HPV-positive, HPV-negative, we’re really beginning to subdivide the disease into smaller and smaller cell groups, based on molecular phenotype.
Tanguy Y. Seiwert, MD: You’re exactly right. Even within each of these subgroups, or these HPV-positive and HPV-negative tumors, there are further subtypes. We’ve actually looked at expression subtypes. It seems like there’s a group of HPV-negative tumors that are heavily hypoxic, have a lot of EGFR signaling. We call this a basal phenotype. We actually don’t know if they do any differently with certain therapies, but it’s an active area of research. We then also have tumors that are inflamed. In fact, we were one of the first groups to describe this inflamed phenotype. We’ve actually known this for other cancer types, like melanoma, before. But there clearly is a subgroup of inflamed tumors in HPV-positive and HPV-negative tumors. And we do know, as of recent, that that has major implications for novel therapies, such as immunotherapy.
Transcript Edited for Clarity
