The hunt for human papillomavirus in head and neck cancer is getting close enough to its quarry to inspire visions of clinical benefit.
At Johns Hopkins Oncology Center, where Maura Gillison, M.D., and colleagues report finding a likely causal association between HPV and oropharyngeal cancers (see p. 709), plans are under way to test HPV treatment vaccines in patients with these tumors. The trial could begin in about a year, said Johns Hopkins immunologist Drew Pardol, M.D.
Several HPV treatment vaccines are in trials for cervical cancer around the world, but this is likely to be the first in head and neck patients.
Fueling hope for the vaccines are indications in the current study that the HPV-positive tumors may form a distinct subset of head and neck cancer with its own carcinogenic pathways. For example, most of the HPV-positive tumors in the study occurred in the oropharynx (the tonsils, soft palate, posterior pharynx, and base of tongue). Of these, all but two were in tonsillar tissue, which shares characteristics with the transformation zone in the cervix, where HPV is known to cause cancer.
Moreover, the 62 HPV-positive tumors in this study25% of the 253 caseshad other important features in common. Compared with other head and neck cancers, they were more likely to have basaloid histology, fewer p53 mutations, less association with alcohol and drug use, and a better prognosis.
Separate studies have pointed to some of these features, said Keerti Shah, M.D., an international HPV expert who is one of the Johns Hopkins authors. But this appears to be the first study to identify all these features in one cohort, and it gives a strong boost to the idea that HPV-positive oropharyngeal cancer is a distinct category of head and neck cancer. "What I find most convincing is that it all fits together," Shah said.
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Based on these data, the researchers have started planning a vaccine trial with patients who fall into this category. Pardol said that the protocol is still under discussion but will probably combine vaccine therapy with chemotherapy. Animal studies have suggested "that chemotherapy and vaccines can synergize very dramatically," he said.
Johns Hopkins has received funding to manufacture three different treatment vaccines through the National Cancer Institutes Rapid Access to Intervention Development (RAID) program, Pardol said. The original intent was to use them for cervical cancer trials only, but the plan is now being enlarged to include HPV-positive oropharyngeal patients.
Two of the vaccines were created at Johns Hopkinsone of them a naked DNA vaccine, the other a recombinant vaccinia vaccine. The third uses Listeria monocytogenes as a vector and was created by Yvonne Patterson, Ph.D., at the University of Pennsylvania Cancer Center, Philadelphia. All are targeted at HPV16, the type of the virus found in 90% of oropharyngeal cancers in the study, and all are candidates for use in the trial, Pardol said.
While the Johns Hopkins researchers are certain enough of the link between HPV and oropharyngeal cancer to go ahead with a trial, they acknowledge that debate on this point continues outside of Baltimore. "As an individual, I think there is a causal association, but the field is still not completely convinced," said Shah.
One reason for skepticism in the past has been that HPV is a very common virus and "was easy to find by mistake," said NCIs Mark Schiffman, M.D. Also, polymerase chain reaction, the method commonly used to detect it, is very apt to turn up false positives. Earlier findings of HPV in head and neck cancers were wildly inconsistent, ranging from almost none to 100%. "The literature was very confusing," said Karl Münger, Ph.D., who studies HPV at Harvard Medical School, Boston.
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Also convincing, Münger and Wong said, are the data showing that HPV-positive, oropharyngeal cancers have molecular and histopathologic characteristics and risk factors that set them apart from other head and neck cancers. "It makes a nice, clean, well-done package," Münger said in an interview.
International Data
Skeptics and believers will soon have more data to ponder from a large international casecontrol study being conducted by the World Health Organizations International Agency for Research on Cancer, Lyon, France. Its results could be available this year, said IARC principal investigator, Rolando Herrero, M.D.
Herrero said investigators have finished collecting 1,700 head and neck tumor samples from patients in various countries, including Italy, Spain, Northern Ireland, Cuba, Poland, India, Sudan, Canada, and Australia. A central laboratory in Amsterdam is now testing biopsied tissue and exfoliated cells for HPV.
In addition to hunting for the virus with PCR, the IARC investigators are testing for antibodies to E6 and E7, the oncologic proteins expressed by HPV16. They also are looking for differences in histology and p53 mutations between the HPV-positive and HPV-negative tumors and for markers of genetic susceptibility, Herrero said.
Another infusion of new data will come from a 5-year, 1,000-patient prospective study at Johns Hopkins, now in the planning stage. Gillison said that this study will gather detailed information on lifestyle, prognostic factors, response to treatment, survival, and family history of head and neck cancer patients with and without HPV.
The prospective study will also be looking at factors that may someday affect management of head and neck cancers. This is an area where believers allow themselves to envision a dayalbeit far in the futurewhen HPV status might have a range of clinical implications.
For instance, the study will determine whether HPV-positive oropharyngeal tumors respond better to chemoradiation than others, Gillison said. If so, HPV status might some day influence the choice of organ-sparing treatments.
Other possible clinical benefits, she speculated, could relate to monitoring and screening. The prospective study will follow patients HPV antibody levels and compare them with outcomes. If there is a relationship, and it is borne out by other studies, antibody levels could turn out be useful in monitoring for recurrence. And if the lifestyle portion of the study confirms that HPV-positive oropharyngeal patients have a distinct risk profile, screening of high-risk populations might some day be feasible.
Many studies lie between the current data and realization of these hopes. But in a field that for 30 years has had little improvement in patient outcome, such visions are still welcome.
"Prognosis is now so poor that anything you could do would be good," Shah said.
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