Human Papillomavirus and Oral Cancer - Looking Toward the Clinic

6/18/2008
web-based article
Caroline McNeil
JNCI Journal of the National Cancer Institute 2008 100(12):840-842 Head and neck cancer researchers are considering clinical studies, including a proposed cooperative group treatment trial, that would investigate the link between human papillomavirus (HPV) and some oral cancers. Although the studies are still in the planning stage, they mark a new turn toward the clinic for an area that up to now has centered mostly on epidemiologic and laboratory studies.

Over the past decade, population studies have established an association between HPV and some tumors in the oropharynx (tonsils, soft palate, posterior pharynx, and base of tongue). Much remains unknown about the biology and natural history of oral HPV infection, but evidence of its association with these tumors is so strong that the International Agency for Research on Cancer concluded, in a monograph published in December, that there is "sufficient evidence in humans for the carcinogenicity of HPV16 in the oral cavity and oropharynx."

Now researchers are beginning to ponder the clinical implications of this link. Especially intriguing to many are data suggesting that HPV-positive oropharyngeal tumors respond better to treatment than HPV-negative tumors. That finding has given rise to important clinical questions, including the one to be addressed in the proposed trial: Can HPV-positive tumors be treated less aggressively than HPV-negative tumors because of their increased sensitivity to chemotherapy and radiotherapy?

"That's the fundamental question," said Arlene Forastiere, M.D., a professor at the Johns Hopkins Kimmel Cancer Center in Baltimore and a leader in the Eastern Cooperative Oncology Group, which is discussing the possibility of such a trial. "Should they be treated the same or differently?"

The difference in response rates is not the only aspect that sets HPV-positive tumors apart from HPV-negative tumors. Studies suggest that the tumors have different molecular and histologic features, that HPV-positive patients survive longer, and that their risk factors and demographics are distinct. HPV-positive patients are more likely to be young and less likely to smoke cigarettes or use alcohol than HPV-negative oral cancer patients. A prospective study published last year in the New England Journal of Medicine showed that HPV-positive tumors were strongly associated with multiple oral sex partners. Most recently, a case–control study ( J Natl Cancer Inst 2008;100:407–20) showed that HPV-positive oropharyngeal tumors are not influenced by alcohol or tobacco use, setting them apart from HPV-negative tumors, which are strongly associated with drinking and smoking.

"The risk factors are completely distinct and do not overlap," said Maura Gillison, M.D., Ph.D., a Hopkins cancer researcher and lead author on this study as well as the New England Journal of Medicine article. "These are actually completely different cancers that happen to occur in the same place," she said.

Others demur. This is "very groundbreaking work," said Jatin Shah, M.D., chief of the head and neck service at Memorial Sloan-Kettering Cancer Center in New York, "but it remains to be proven that these are distinct pathological entities." Tissue samples from HPV-positive and HPV-negative tumors look alike, he argues. And although HPV-positive patients have a better chance of responding to chemoradiation, the reasons are unknown. "This is a very provocative question," he said. "We need more research in the lab to answer it."

The question is particularly urgent in oropharyngeal cancer because of the acute and prolonged toxicity of current treatments, Shah said. The treatment can result in lifelong problems with swallowing and speech. And for HPV-positive patients, who are more likely to be young, that can mean many decades of severely impaired quality of life.

Still Hypothetical

Nevertheless, Shah and others warn against modifying the standard treatment now. Forastiere, who chairs the head and neck committee of the National Comprehensive Cancer Network, said that "it would be premature to make practice changes ... quite dangerous, really." The cancer network's 2008 treatment guidelines for orophyryngeal cancer will not mention HPV status, she said. "The next steps are really in clinical trials."

The link between HPV and oropharyngeal cancer also raises the possibility of targeting those tumors with a therapeutic vaccine. At Hopkins, Gillison and her colleagues have completed a phase I trial with an experimental treatment vaccine and are now analyzing the data. After 2 years of follow-up, she said, all 18 patients in the trial were doing well.

And if further studies confirm that HPV-positive patients have better response rates and survival, their improved prognosis could affect the staging system for head and neck cancers. Though a long way off, that possibility is already the subject of conjecture. Gillison said that, someday, HPV-positive and HPV-negative tumors might be staged as two separate diseases, in the way that small-cell and non–small-cell lung cancer are.

Shah, who chairs the head and neck section of the American Joint Committee on Cancer, which develops, maintains, and revises the tumor–node–metastasis staging system used in most cancers, said that one possibility would be to consider HPV status as an additional factor that influences prognosis. This factor may be considered in the future, he said, and could be similar to the way additional factors affect stage in other cancers. In thyroid cancer, for instance, anyone younger than 45 years is downstaged to a stage 1 or 2, even with distant metastases.

But HPV's effect on oropharyngeal staging is still hypothetical, Shah emphasized. The joint committee is not considering any changes to the current system. "The time may come when HPV status will be a factor," he said, "but there needs to be a lot more science before that."

Prevention and Screening?

The link between HPV and oropharyngeal cancer also has potential implications for prevention. Will it ever be possible, for instance, to detect precancerous changes in the oropharynx, as in the cervix, with the help of HPV-based screening?

Detecting signs of oral HPV infection is not difficult—in oral rinses, for instance. But finding evidence that the viral DNA has been integrated into oropharyngeal basal cells and identifying submucosal, premalignant changes before they become visible is "a bit trickier," Gillison said.

An even more fundamental barrier to screening is a lack of knowledge on how, or even whether, persistent oral HPV infection progresses to premalignant changes in the oropharynx.

"We don't know what the infection looks like in premalignant cells. We don't know if premalignant lesions in the oropharynx relate to HPV," said Aimee Kreimer, Ph.D., in the division of cancer prevention at the National Cancer Institute in Bethesda, Md. "It's so new. We don't know the natural history of oral HPV infection."

Shah said that studies are needed to show whether oral HPV infection progresses to dysplasia, as it does in cervical cancer. Doing so would take a prospective, longitudinal study of people with HPV infection, followed by visual detection of premalignant changes, he said. Or researchers might look for surrogate markers of progression by using random biopsies. "I don't know if anyone is doing this, but it would be an exciting project," he said. "It's the logical next step."

One smaller step toward understanding the natural history of HPV oral infection is a study, now in a pilot stage, designed to look at the persistence of these infections, Kreimer said. The study will be nested in a larger study—led by Anna Giuliano, Ph.D., at the H. Lee Moffitt Cancer Center in Tampa—which is monitoring men to evaluate anal and penile HPV infections.

Primary prevention of oropharyngeal cancers is another possibility that intrigues HPV researchers. Current HPV vaccines, designed to prevent cervical cancer, could theoretically prevent HPV-positive oropharyngeal cancers as well. Both Merck's Gardasil and GlaxoSmithKline's Cervarix (which was approved in Australia but not yet in the U.S.) target HPV16, which is implicated in most HPV-positive oropharyngeal cancers. And animal studies suggest that vaccination will prevent oral cancers. Hopkins researchers have proposed a prevention study to Merck, but when contacted for this article, a company spokesperson said that it is not currently working on plans for such a trial.

However, other studies may provide some data on this issue. Kreimer said that the NCI is considering adding an oral HPV component to its follow-up study of women in Costa Rica who participated in a trial of GlaxoSmithKline's prevention vaccine. The study would compare the prevalence of oral HPV infection among women who received the vaccine with women who did not.

More studies—of all kinds—are likely. The NCI head and neck steering committee will convene a state-of-the-science meeting in November to help identify and prioritize research needs, said Claudio Dansky Ullmann, M.D., NCI's lead for head and neck cancer trials, who serves on the steering committee. "We will bring the top experts in this area to discuss the current status of things and, we hope, to lay a platform plan for the development of future translational and clinical studies to advance the field," he said.

And there seems little doubt that some of those studies, such as the proposed treatment trial, will explore whether HPV-positive and HPV-negative patients should be treated differently. "We find the data indicating that HPV-positive and HPV-negative cancers are distinct disease entities to be compelling," Forastiere wrote in an e-mail. "Consequently, we are factoring this into clinical research questions and trial designs going forward." (www.oralcancerfoundation.org)

Primary Tumors Can Drive the Growth of Distant Cancers

6/23/2008
web-based article
staff
Biocompare Life Science News (www.biocomare.com) Primary tumors can encourage the growth of stray cancer cells lurking elsewhere in the body that otherwise may not have amounted to much, according to a new study in the June 13 issue of the journal Cell, a publication of Cell Press. As people age, most may have such indolent cancer cells given the sheer number of cells in the body, although their rarity makes them impossible to detect, the researchers said.

The primary tumors under study, which were derived from human breast cancers, seem to "instigate" the growth of other cancers by mobilizing bone marrow cells, which then feed the secondary tumors' growth, they report.

One key to the process is the secretion of a substance known as osteopontin by the instigating tumor, a finding that may have therapeutic implications. Indeed, the researchers noted that osteopontin is present at elevated levels in women with metastatic breast cancer, supporting the notion that the new findings may hold clinical significance.

"If metastases depend on stimulation by primary tumors, interception of the signal through neutralizing antibodies" might block cancer spread, said Robert Weinberg of the Massachusetts Institute of Technology. "That's still speculative, but it's an interesting idea to ponder," he added, noting that treatments today don't specifically target metastases, which are responsible for the vast majority of cancer deaths.

The researchers noted that while the effects of the tumor microenvironment has been much studied, much less was known about how the systemic environment in the body contributes to tumor growth. Several earlier reports had shown that assorted bone marrow-derived cells can be incorporated to various extents into the supportive framework, or stroma, of tumors. However, it wasn't clear whether tumors actively recruit stromal cells by directly perturbing other cell reservoirs, such as the bone marrow, or whether tumors are just passive recipients of stromal cell precursors that normally circulate throughout the body.

In the new study, the researchers injected "instigating" human tumor cells into mice along with indolent "responding" cancer cells also derived from humans. Those indolent cells formed vigorously growing tumors only in the presence of the instigating tumor cells, they reported. They found further evidence that the instigating tumor somehow perturbs the makeup of the bone marrow, although Weinberg said they don't really know how that happens. They also show that osteopontin is necessary to the process, but that it does not act alone.

Finally, they showed that the same instigation process can encourage the growth of disseminated metastatic cancer cells. Instigating breast tumors in the mice also drove the growth of implanted fragments of human colon tumors, a finding that they said shows the generality of the physiologic signaling.

Nonetheless, the researchers said they don't yet know how universal this systemic instigation of tumor growth might be. Still, the findings challenge the "prevailing view that primary tumors suppress the growth of derived metastases," Weinberg said. "We argue they can foster cancer's spread by activating bone marrow that is then recruited by distant metastases."

The findings also have important implications for the preclinical study of human cancers, Weinberg emphasized.

"The ability of instigating tumors to foster the growth of a human colon tumor surgical specimen underscores the powers of systemic instigation," the researchers wrote. "Indeed, to our knowledge, methods to expedite the growth of human tumor surgical specimens in vivo have not been previously described. These results suggest that the presently described procedure can be used to study aspects of human tumor biology that would otherwise be difficult if not impossible to study.

"In the longer term, identification of additional tumor-derived factors that perturb the host systemic environment in one way or another may allow one to predict the effects that a given primary tumor type has on the outgrowth of indolent cancer cells that have disseminated to distant sites."