Increased exposure may be cause of rising HPV-related cancer rate

Comprehensive data from the CDC, National Cancer Institute and the North American Association of Central Cancer Registries continue to show a decline in both incidence and mortality rates for most cancers in the United States.

There are three notable exceptions: oropharyngeal, anal and vulvar cancers related to HPV. The most dramatic increase is among cancers of the oropharynx, the region of the throat that includes the tonsils, uvula and the base of the tongue.

A Surveillance Epidemiology and End Results (SEER) registry review conducted by Jemal and colleagues, published earlier this year in the Journal of the National Cancer Institute, showed that HPV DNA was detected in 71.7% of oropharyngeal tumors diagnosed between 2000 and 2004, more than four times higher than the 16.3% prevalence rate reported between 1984 and 1989.

Incidence rates also have increased in Canada and several European countries. Meanwhile, rates of oropharyngeal cancers attributable to other common causes, including smoking and alcohol consumption, are on the decline, according to NCI.

There is some encouraging news: Data suggest the prognosis is good for patients with HPV-associated oropharyngeal cancers.

“The expectation is that the vaccines will prevent oropharyngeal cancers in future, but we are not there yet,” David Adelstein, MD, a staff physician in the department of solid tumor oncology at Cleveland Clinic’s Taussig Cancer Institute, told Infectious Disease News. “The improved prognosis for these patients is independent of better performance status and other risk factors, but it is still unclear as to why.”

Infectious Disease News discussed the trend with several researchers. Most agreed that changing sexual behaviors among Americans likely contribute to the increase in oropharyngeal cancers, but the specific connection has yet to be clearly defined.

Impact of HPV vaccine

HPV vaccines are known to protect against anal, vulvar, cervical and vaginal cancers. However, it is too early to tell whether the recommendation that all teens undergo HPV vaccination will affect incidence rates of other HPV-associated cancers. However, slower-than-expected uptake rates for vaccinations among both girls and boys have many in the field concerned.

“I see a huge reluctance on part of physicians to strongly recommend the HPV vaccine to adolescents,” Janet A. Englund, MD, professor of pediatric infectious diseases at Seattle Children’s Hospital, told Infectious Disease News. “We know the vaccine works well and we know it works even better in younger teenagers. We have to get the vaccine administered earlier, but as a country, we’re doing a terrible job of it.”

A study published in Cancer this year by Jain and colleagues showed that just 32% of girls aged 13 to 17 years received the full three-dose course of the HPV vaccine in 2010. Rates were as low as 14.1% among the uninsured. This is in contrast to other countries, especially the United Kingdom and Australia, where the vaccine is given in schools with parental permission, Englund said. In these countries, the vaccination rates are more than 95%.

HPV vaccination rates for boys remain in the single digits, Amy E. Leader, PhD, assistant professor in the department of medical oncology at Thomas Jefferson University, said in an interview.

“For the boys, it is somewhat understandable because, practically speaking, the vaccine has really only been around for a year or so,” Leader said in an interview. “But what we have heard from parents is that their teenagers are ‘too young to be having discussions about sex.’ The reality is that we want them to be vaccinated before they have sex. Parents don’t see that connection.”

Changing sexual habits

The oropharyngeal cancer patient population has evolved to include a higher percentage of nonsmokers and nondrinkers in their mid-40s and early 50s. The traditional population with this type of cancer is older men who are smokers and drinkers

According to Carol L. Brown, MD, director of the office of diversity programs in clinical care, research and training at Memorial Sloan-Kettering Cancer Center, the increase may be attributed to changing sexual habits coinciding with an epidemic of this virus

Maura L. Gillison, MD, PhD, professor of medicine, epidemiology and otolaryngology and Jeg Coughlin Chair of cancer research at The Ohio State University Comprehensive Cancer Center — Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, said more people are being exposed to the virus, and therefore, more cancers are developing.

“There is no evidence that the infection is becoming more virulent because this has proven to be a very stable virus, so we must begin looking at how exposure has changed,” Gillison told Infectious Disease News.

According to Robert I. Haddad, MD, the disease center leader in the head and neck oncology program at Dana-Farber Cancer Institute, one of the most significant issues in the clinic is risk to the partner.

“This is a delicate discussion, one that can have a profound effect on relationship or marriage,” Haddad said in an interview. “At the moment, we are not seeing an increased risk for cancer in the partner, but the data may show us that eventually.”

Still, efforts to reduce sexual transmission of the virus may be unrealistic, and it is also just a small piece of the puzzle, Adelstein said.

“The likelihood that fear of oropharyngeal cancer will alter sexual practices is nonexistent,” he said. “Where you can intervene is with the use of the vaccination.”

Vaccine protection

Studies have shown that the vaccine prevents both precancerous lesions in the cervix and anus, and genital warts, both of which are surrogate markers for cancer, Englund said. As for its effect on the prevention of other cancers, research is ongoing.

However, there is not yet any evidence about how long the vaccine’s protection lasts, according to Diane Harper, MD, MPH, MS, professor in the departments of community and family medicine, obstetrics and gynecology and informatics and personalized health at University of Missouri-Kansas City School of Medicine.

“There is no evidence to show us that those who receive the HPV vaccine now will have a decreased incidence of cancer in the future,” Harper told Infectious Disease News. “If the vaccine’s protection doesn’t last at least 15 years, then booster shots will be needed, which no one has addressed yet. If the vaccine’s protection does wane, then people who have received the vaccine are going to think they are protected against HPV, when they can in fact acquire a new HPV infection.”

The challenge for clinicians is helping parents view the HPV vaccination in a manner similar to other disease prevention efforts.

“People have no problem getting their children vaccinated for pertussis or meningococcal disease, but the sexual nature of HPV can make everyone involved uncomfortable,” said Martin Mahoney, MD, PhD, associate professor in the departments of health behavior and medicine at Roswell Park Cancer Institute. “Many physicians don’t want to broach the subject of HPV vaccine because it’s sexualized, and parents and teenagers are happy to avoid the subject for the same reason. This has to change.”

Although the fact that HPV is transmitted sexually cannot be ignored, the cancer prevention component must be part of the message, Mahoney said.

“We are vaccinating now to prevent cervical cancer among women in their 40s and 50s,” he said. “If parents understand this a little more clearly, it may influence their decision-making process.”

There also may have been a missed opportunity to minimize the sexual implications of the vaccine at the time it was introduced, Brown said.

“There is no avoiding the fact that HPV is an STD,” she said. “But if the initial message emphasized the fact that the vaccine may prevent you from getting cancer when you get older, we might be looking at some different numbers right now.”

Improving uptake

In a study published in Pediatrics, Darden and colleagues found that the number of parents who are worried about the safety of the HPV vaccine rose from 4.5% in 2008 to 16.4% in 2010. The results also showed that 40% of parents surveyed in 2010 said they did not intend to have their teenage daughters vaccinated. They observed no similar patterns for other vaccines.

“Clinicians are also concerned about what the parents may say,” Leader said. “Providers need to be more proactive in having this discussion.”

Hopkins and colleagues published data in Vaccine that suggested school-based opt-out programs achieve the highest coverage, but success of vaccination programs depends on the support of the public and of health care professionals.

But the major issue, according to Adelstein, is education.

“There is all kinds of misinformation out there regarding autism [and the] risk of severe reactions, he said. “We need to educate parents.”

Part of the problem is that the vaccine was introduced through a marketing campaign rather than through providers, Gillison said.

“If you educate the provider, and then the provider advocates in the community, everyone lines up their children to get the vaccine,” Gillison said. “A marketing campaign is a different story. The key is to frame the recommendation as a public health issue. If you tell parents that the vaccine prevents cancer, they respond. Telling them it prevents an STD is not as impactful.”

The gender-specific recommendation at the time the vaccine was introduced also may have contributed to confusion among parents and the public, Mahoney said. Although guidelines issued in 2009 recommend the HPV vaccination for boys, confusion remains.

“When there is this kind of confusion, as there was in 2006 when the vaccine was first recommended [for girls], people tend to avoid the issue altogether and move onto something else,” Mahoney said. “This is reflected in the uptake levels.”

There is misinformation about the vaccine even among providers, Gillison said.

“We have heard pediatricians tell parents that their daughters do not weigh enough to receive the vaccine, which is incorrect,” she said. “Another provider said he would not give the vaccine because the daughter was not yet menstruating, which is also incorrect. The message needs to be more consistent, even in the health care community.”

Screening and early detection

As the vaccine debate continues, issues regarding screening also have sparked debate.

“In the United States, we are seeing firsthand in cervical cancer how primary prevention with a vaccination and secondary prevention with a screening program can work,” Gillison said. “We are seeing a clear public health benefit in reduced cervical cancer incidence rates. The challenge is to apply this to other HPV-related cancers.”

According to Harper, Finland had a very successful Pap smear screening program, and about 10 years ago, the incidence of cervical cancer dropped to almost zero among women aged 25 to 30 years. However, the rate of cancer has increased 10-fold in the past 10 years in this age group.

“I see a lot of young patients who think that they are protected because they are vaccinated, so they don’t need Pap smears anymore,” she said. “We don’t know how long the vaccine protects against HPV. Physicians need to tell their patients that vaccination is a great option for at least 5 years of protection, but they need to continue with Pap screening.”

However, screening methods for HPV-related oropharyngeal cancers remain uncertain.

“We don’t know what the precursor lesions are like,” Gillison said. “We can’t make a visual identification because they are not on the surface. Figuring out how to detect and eliminate the precursors is critical. It is possible because this is what we do on the cervix, but we are not there yet in the oropharynx.”

Prognosis and treatment

In The New England Journal of Medicine, Ang and colleagues published data from a retrospective analysis that examined tumor HPV status and survival of 323 patients with stage III or IV oropharyngeal squamous cell carcinoma. The researchers determined that 63.8% of patients had HPV-positive tumors. Three-year overall survival among those patients was 82.4% vs. 57.1% among patients with HPV-negative tumors.

They concluded that tumor HPV status is a strong and independent prognostic factor for survival among patients with oropharyngeal cancer.

Even with more encouraging baseline characteristics and advanced procedures, oropharyngeal cancers are more difficult to treat than cervical cancers, which emphasizes the importance of prevention, Brown said. Prevention, in turn, can help ensure that the incidence rates of HPV-associated oropharyngeal cancers do not continue to increase significantly.

“HPV-related cancers represent about 3% of the overall cancer burden,” Mahoney said. “Compared with other malignancies, this is a relatively small number. We need to pay attention to the information we have in order to keep it that way.” – by Rob Volansky and Emily Shafer

Disclosure: Adelstein, Brown, Haddad, Harper, and Leader report no relevant financial disclosures. Englund previously served as a consultant to GlaxoSmithKline. Gillison serves as a consultant to GlaxoSmithKline, and previously worked as a consultant to and received research funding from Merck. Mahoney serves as a consultant to and speakers’ bureau member for Merck, and he is a former consultant to and speakers’ bureau member for GlaxoSmithKline.

 

Do HPV-related oropharyngeal cancers have better prognoses because of tumor biology or patient lifestyle?

Biology likely defines the improved prognosis.

HPV-positive oropharynx cancers are rising dramatically in incidence, and they have become the most common subtype of head and neck cancers seen in North America and many other countries.

The silver lining of this disease is that it carries a better prognosis than its HPV-negative counterpart.

Until large data sets were analyzed, there was controversy whether this improved outcome was due to the favorable demographics associated with HPV-positive cancers. These patients tend to be younger, nonsmokers, and they also tend to have fewer comorbidities. Moreover, the disease is more likely to present with smaller tumors but with early lymph node involvement.

However, with retrospective examination of large randomized trials that could account for these factors in multivariate analysis, it is apparent that patient or disease characteristics could not account for the improved outcome.

HPV-positive cancers fare better based on the fact they are HPV positive. The solution to this observation comes from deciphering the molecular biology of HPV-positive cancers. From gene expression and exome sequencing data, it is clear that HPV-positive cancers harbor fewer mutations in general than their negative counterparts, and they almost never carry alterations in critical tumor suppressor genes associated with aggressive behavior, such as p53 or p16.

Therefore, it is almost certainly the intrinsic biology of HPV-positive cancers that defines their better prognosis. Now we must meet the challenge of treating these patients with approaches tailored to that difference in biology and improve outcomes even further.   

Ezra Cohen, MD, FRCPC, is an associate professor in the department of medicine, co-director of the Head and Neck Cancer Program, program director of the Hematology/Oncology Fellowship Program and associate director for education at the University of Chicago Comprehensive Cancer Center. He also is editor-in-chief of Oral Oncology. He can be reached at 900 E. 57th St., Room 7146, Chicago, IL 60637; email: ecohen@medicine.bsd.uchicago.edu. Disclosure: Cohen reports no relevant financial disclosures.

 

Tumor biology and lifestyle both likely contribute.

These cancers don’t appear to be staged all that much earlier than HPV-negative malignancies. We tend to see them staged at III or IV.

There certainly are differences in the biology of HPV-negative and HPV-positive tumors. Although patients generally have a profound history of alcohol and/or tobacco use or other associated carcinogens in HPV-negative tumors, there is a different tumor phenotype. Smoking is more prevalent among patients with HPV-negative tumors. This, in turn, is associated with different genetic changes than we see in HPV-positive tumors. The HPV-positive tumors come from a viral etiology, and those patients tend to have better health behaviors.

That said, in our research, we often ask ourselves whether it is the healthy lifestyles of these patients that lead to the improved tumor biology and better prognosis, or whether it is the underlying biology of the tumor itself.

The answer, likely, is both. In our data, patients with HPV-positive tumors are more likely to be married, have healthier diets and have a higher BMI, which helps them withstand the rigors of therapy associated with head and neck cancers.

Undoubtedly, both lifestyle and tumor biology are so intertwined that it is probably a little bit of both. There is a lot of interplay over the life span of these tumors.

Laura S. Rozek, PhD, is assistant professor in environmental health sciences at the University of Michigan School of Public Health. She can be reached at 6630 SPH Tower, 1415 Washington Heights, Ann Arbor, MI 48109-2029; email: rozekl@umich.edu. Disclosure: Rozek reports no relevant financial disclosures.