Barbara A. Burtness, MD: I think we’ve certainly learned a lot more about the biology. There have been a couple of important sequencing papers, and the Cancer Genome Atlas now has more than 500 head and neck cancers in it. We clearly see, as Josh mentioned, that there’s a difference in the mutational profile of the HPV-associated and the HPV-negative cancers. In terms of what might be actionable, thinking about ways that head and neck cancer might be like non—small cell lung cancer; it hasn’t been so obvious that there are a large number of specific genetic drivers. The one thing that probably leaps out is PIK3CA, and we have seen some evidence for that activity with PI3 kinase inhibitor buparlisib, but it is not at all clear, actually, that that was linked to the presence of these mutations.

One of the challenges for head and neck cancer has been that many of the mutations that we find are in tumor-suppressor genes. And there is often not—or to date, there has not been—a medication that can directly restore the function, say, of mutated p53. There were some patients who went in to the MATCH trial. There were arms that targeted PTEN abnormalities and FGFR. But I think that our increasing understanding of the complexity of the mutational profile, both in HPV-positive and HPV-negative disease, has not led to immediately using targeted therapy in head and neck cancer the way it has in some other solid tumors, which is not to say that that is not still something to pursue.

Ezra Cohen, MD: Absolutely. And I know that there are groups that are pursuing even the tumor suppressor genes. Barbara, I think ECOG has a study looking at disruptive p53 mutations and how they may impact the choice of therapy. That has just initiated, I believe.

Barbara A. Burtness, MD: There is an observation that if a p53 mutation is disruptive for patients who’ve had good surgery, with negative margins, and then got appropriate risk-based adjuvant therapy, the patients with that disruptive p53 mutation are more likely to die. There’s a lot of preclinical evidence that says they are more radio-resistant, and there is some suggestion that you can overcome that with platinum.

So, this is a post-op study. All of the patients get a free genome profile as part of the enrollment, and then they are stratified by their p53 status. I guess it’s also interesting to think about how Jared said that HPV-positive patients overall do so much better than the HPV-negative patients. And yet, within the HPV-positive patients, we do recognize that the patients with the bulkiest tumors—and then, in this sort of unexplained finding, the patients who have been smokers in their lifetime, who have more than 10 pack-years of tobacco exposure—have a higher risk of recurrence, even with good curative therapy. We’ve been hoping to try to find a molecular signature that could, first of all, help explain that finding and, second of all, maybe be a better test for who needs intensified therapy or who’s a candidate for de-intensified therapy than just asking the patient, “How much did you smoke?”

And there are these very recent data that came out of the TCGA suggesting that patients who have mutations in TRAF3 and CYLD, which can lead to activation of kappaB signaling, may be a group that is particularly likely to do well. So, that’s certainly something that needs to be confirmed by looking at specimens from treated patients. But I think we are beginning to make some inroads on the challenge of finding a good molecular signature.

Ezra Cohen, MD: And certainly, Jared, the data that you discussed regarding the idea of putting biomarkers together, including a biomarker looking at tumor-infiltrating lymphocytes, were an attempt to do that. And I think, Barbara, you were quite right: we’ll see a lot more of those going forward.

Josh, I want to turn back to you. You talked about HPV and we see that, without a doubt, as a prognostic marker. There is another virus, of course, that’s associated with a type of head and neck cancer. Maybe you can just tell us a little bit about that.

Joshua M. Bauml, MD: Absolutely. Epstein-Barr virus, or EBV, is another critical virus when discussing, usually specifically, nasopharyngeal cancer, though it can impact other disease sites as well. The reason why that becomes relevant when examining the literature and treating patients is that EBV can serve as a biomarker for how the patient is doing. So, there are a lot of great data that have come out of Asia looking at following patients with EBV-positive nasopharyngeal cancer and evaluating, prospectively, quantitative Epstein-Barr virus. And that’s very useful. I had a patient in my clinic just a couple of months ago, where they had something that looked a little bad on the CAT scan but she was doing very well. We did an EBV titer and it was 0; it was very reassuring. We did a biopsy, but we were more reassured by the biopsy with the EBV negativity.

The other reason that EBV becomes important is that nearly all of the nasopharyngeal cancer in Asia is related to Epstein-Barr Virus, whereas the nasopharyngeal cancer that occurs in the United States is still largely a smoking and drinking related disease. And so, extrapolation of data from Asia nasopharyngeal cancer is somewhat problematic, and we need to know exactly what we’re talking about when a patient comes in with nasopharyngeal cancer.

Ezra Cohen, MD: So, what I’m hearing you say is that there are some patients in the United States who can have EBV-related nasopharynx cancer.

Joshua M. Bauml, MD: Oh, absolutely, yes.

Ezra Cohen, MD: But on the other hand, there’s also a group that has more smoking-related and tobacco-related nasopharynx.

Joshua M. Bauml, MD: Yes.

Ezra Cohen, MD: And we need to differentiate that early because they really are different diseases.

Joshua M. Bauml, MD: That’s right. That’s exactly right.

Ezra Cohen, MD: And so, all of this discussion really has fed into a new staging system for us in head and neck cancer, especially when we talk about HPV-related disease.

Transcript Edited for Clarity