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Immune Response to HPV16-Driven Tumorigenesis May Be Detectable Before Clinical Diagnosis of Oropharyngeal Squamous Cell Carcinoma

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Key Points

  • HPV antibodies were present in only 0.4% of people in the control group (22 of 5,814) but were detected in 26.2% of patients with oropharyngeal squamous cell carcinoma (195 of 743).
  • Antibodies were present in 27.2% of white people before a diagnosis of oropharyngeal squamous cell carcinoma (191 of 701) and in 7.7% of black people (3 of 39).
  • HPV16 antibodies tended to appear in people between about 40 to 80 years old—the median age at which antibodies were detected was 52 years—whereas the median age of diagnosis with oropharyngeal squamous cell carcinoma was 62.

An international group of researchers has found that antibodies to the human papillomavirus type 16 (HPV16) may develop in the body between 6 to 40 years prior to a clinical diagnosis of oropharyngeal squamous cell carcinoma, and their presence indicates a strong increased risk of the disease. These findings were published by Kreimer et al in Annals of Oncology.

The study also found that having HPV16 antibodies increased the risk of oropharyngeal squamous cell carcinoma far more in white patients than in black patients (nearly 100-fold in white people vs 17-fold in black people). Patients with HPV-associated throat cancer tend to respond better to treatment than those whose cancer is not associated with the infection; the researchers say this may partly explain the worse survival rates among black patients.

Background and Methods

Lead author Mattias Johansson, PhD, a cancer epidemiologist at the International Agency for Research on Cancer (IARC) in Lyon, France, said, “Importantly, the proportion of [oropharyngeal squamous cell carcinomas] caused by HPV16 has been increasing over the past few decades, particularly in men, and in some countries, the overwhelming majority are now caused by the virus. Investigating the range in time prior to diagnosis in which HPV antibodies develop is important to understand how many years an individual who tested positive would be at increased risk, and also gives important insight into the natural history of the disease. In this study, we found that antibodies can, in some cases, develop several decades prior to diagnosis of cancer. If rates of [oropharyngeal squamous cell carcinoma] continue to rise in the future, this biomarker could provide one means to identify individuals at very high risk of the disease who may benefit from specific preventive measures.

Researchers from Europe, North America, and Australia who were part of the HPV Cancer Cohort Consortium analyzed 743 patients with oropharyngeal squamous cell carcinoma and compared them with 5,814 patients without cancer. In the years before any diagnosis of cancer, all patients provided at least one blood sample, which was tested for antibodies against the HPV16 cancer-causing E6 protein; 111 patients provided multiple samples over a period of up to 40 years. The median time between first blood sample collection and a diagnosis of oropharyngeal squamous cell carcinoma was just over 11 years.

Results

Specifically, the team found that HPV antibodies were present in only 0.4% of people in the control group (22 of 5,814) but were detected in 26.2% of patients with oropharyngeal squamous cell carcinoma (195 of 743). Antibodies were present in 27.2% of white people before a diagnosis of oropharyngeal squamous cell carcinoma (191 of 701) and in 7.7% of black people (3 of 39). This means that the presence of HPV16 antibodies was associated with a 98.2-fold increase in the risk of oropharyngeal squamous cell carcinoma in white people and a 17.2-fold increase in black people.

First author of the study Aimée Kreimer, PhD, Senior Investigator in the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, said, “We also found that people diagnosed in more recent calendar years were more likely to have HPV antibodies, which is consistent with what we know about the increase in the proportion of throat cancers that are due to HPV16. Although there were some people with HPV antibodies detected prior to 1995, this was relatively rare.”

The researchers found that HPV16 antibodies tended to appear in people between about 40 to 80 years old. The median age at which antibodies were detected was 52 years, whereas the median age of diagnosis with oropharyngeal squamous cell carcinoma was 62. As there is no suitable, evidence-based way to test for oropharyngeal squamous cell carcinoma before symptoms appear, more research will be needed before HPV16 antibodies could be used to detect oropharyngeal squamous cell carcinoma in its early, presymptomatic stages.

Study Implications

Dr. Kreimer said, “Although HPV16 antibodies could be a way to identify people at very high risk of cancer, we are currently missing the critical next steps in the screening process. Also, even though the antibody marker was very good at discriminating between those who would develop cancer and the controls who would not, with such a rare cancer, many people would still be likely to have a false-positive result.”

Dr. Johansson concluded, “Future studies will focus on the most appropriate way to follow-up individuals who test positive for HPV16 antibodies and whether there is a way to identify premalignant lesions as well as alternative ways of reducing the risk of eventually developing oropharyngeal squamous cell carcinoma. In other words, there is a long way to go before this biomarker can be used in clinical practice. While vaccination against HPV holds promise in preventing HPV-related cancers, we will not see a resulting reduction in throat cancers for several decades.”

The main limitation of the study is the difference between the groups of patients who took part in the study. For example, the group with the longest period of time between first collection of blood and diagnosis of oropharyngeal squamous cell carcinoma came from Norway, whereas other patient groups tended to have fewer blood samples collected over shorter timescales.

Disclosure: For full disclosures of the study authors, visit academic.oup.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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