Progress in Primary and Secondary Prevention of HPV-Associated Noncervical Cancers

Noncervical human papilloma virus (HPV)–associated oral and anal cancers are on the rise in the United States in men and women. The good news is that the HPV vaccine can be used for primary prevention of HPV-associated cancers, and some promising biomarkers have been identified that would advance the search for secondary prevention strategies for these cancers, explained Aimée Kreimer, PhD, Division of Cancer Epidemiology & Genetics at the National Cancer Institute, during the 2013 annual meeting of the American Association for Cancer Research.

“The goal of primary prevention is to remove exposure, and for that we have arrived, because we have prophylactic HPV-16 vaccination. For secondary prevention, the goal is to screen patients and interrupt progression. The future holds promise for secondary prevention of HPV-associated anal and oropharyngeal cancer,” she told listeners at a session on HPV-associated cancers.

HPV causes nearly all cervical cancers and most anal cancers, as well as some head and neck cancers including oropharyngeal cancers. Trends have shown increases over time in the incidence of HPV-associated anal and oropharyngeal cancers in the United States, while HPV-associated cervical cancer is dominant in less-developed areas of the world, she said.

“In more-developed countries, including the US, the gender ratio for HPV-associated cancers is becoming more even. Resources should be directed to men as well as women,” she stated.

Currently, there are 2 prophylactic HPV vaccines: Gardasil (Merck & Co., Inc.), targeted to HPV types 6, 11, 16, and 18; and Cervarix (GlaxoSmithKline), targeted to HPV 16 and 18. Both vaccines are more than 95% effective at cervical sites. Gardasil is effective against anal, vaginal, and vulvar cancers as well as most genital warts in females.

It is also protective in males against most genital warts and anal cancers.

Gardasil is also effective at the penis, but Cervarix has not been evaluated at that site. Cervarix is highly effective against HPV infection at the oropharynx, but Gardasil has not been evaluated at that site.

The Costa Rica HPV-16/18 Vaccine Trial included 7466 women aged 18 to 25 years who were randomized to control vaccine or Cervarix. After 4 years, the efficacy of the vaccine was high against HPV infection at the cervix, anus, and oral sites. Protection from the vaccine persists at the cervix for up to 8 years, but more long-term data are needed for the other sites.

“The vaccine should provide coverage for at least a decade. The immunogenicity of this vaccine looks strong, but longer follow-up is needed,” Kreimer said.

In some countries, including Australia, nationally funded HPV prevention programs have made excellent inroads in eradicating cervical precancer. However, the uptake of the vaccine is inadequate in the US and other countries in the developed world. In the US, only about 10% to 20% of girls aged 11 to 12 years and about 1% of boys in this age range have had the vaccine.

“The current generation at risk for HPV-associated cancer will not be well protected in the US, because of the low percentages of uptake,” she said. “The barriers to uptake of the HPV vaccine need to be explored and addressed.”

Secondary Prevention

“Secondary prevention will remain necessary for the next several decades. There is no validated secondary prevention for HPV-associated cancer beyond the Pap smear at the cervix,” she stated.

To make secondary prevention a reality, a test is needed to detect precancers and asymptomatic cancers at noncervical sites. Effective treatment will reduce mortality.

Kreimer also said there are promising developments for secondary prevention for HPV-associated anal cancer and oropharyngeal cancer.

Although it is still rare, the incidence of anal cancer is increasing. The trajectory of the increase has steepened. In males, 28% of anal cancer is attributable to the HPV epidemic, yet only 1% of female anal cancer is explained by HPV infection. There are no national requirements for screening for HPV at the anus, she said.

It is possible that an anal Pap smear could be used to detect asymptomatic anal cancer, and that the same biomarkers used for cervical cancer would apply at this anatomic site, she said.

Randomized controlled trials are needed to characterize the natural history of anal cancer and to identify effective treatments, she said. It is possible to identify men at high risk, she added.

Regarding HPV-associated oropharyngeal cancer, which is also increasing, L1 antibodies have been identified as markers of exposure to HPV-16, and HPV-16 E6 antibodies are likely to identify this disease.

The European Prospective Investiga-tion Into Cancer and Nutrition (EPIC) study evaluated HPV serologic markers in 400,000 participants. HPV E6 was absent in controls without cancer but was present in 34.8% of oropharyngeal cancers. This study needs replication to establish HPV-16 E6 antibodies as a marker for HPV-associated oropharyngeal cancers. Kreimer said that this marker is present more than 10 years before the development of oropharyngeal cancer.

“The future looks promising for screening for some HPV-associated noncervical cancers. We are enthusiastic about the possibilities of secondary prevention for anal cancer, but better biomarkers are needed. We are enthusiastic about screening for oropharyngeal cancer for the opposite reason—a promising biomarker has been identified. We still need additional studies,” Kreimer stated.

Reference
Kreimer A. Prevention of non-cervical HPV-associated cancers. Presented at: American Association for Cancer Research 2013 Annual Meeting; April 9, 2013; Washington, DC.