Early Detection of Human Papillomavirus–Driven Oropharyngeal Cancer Using Serology From the Study of Prevention of Anal Cancer

Oropharyngeal cancer (OPC) is rare and, in some countries, more than 70% of all cases are caused by human papillomavirus (HPV).¹ The type HPV16 accounts for more than 85% of all cases of HPV–associated oropharyngeal cancer (HPV-OPC).¹ Antibodies to the HPV16 E6 oncoprotein are biomarkers for determining the HPV status of OPC cases, with reported sensitivities of around 90% and specificities higher than 95%.² Antibodies can be detected more than 10 years prior to OPC diagnosis.^1,3 However, their positive predictive value for HPV-OPC is low, at approximately 1% per year.^3,4 Most patients with HPV-OPC also have antibodies to other viral regulatory and oncoproteins (E1, E2, E7)^1-3 and have higher antibody levels than seropositive individuals who do not develop cancer.^1,3 Currently, there is no consensus on HPV-OPC screening,⁴ but including these other variables may improve the specificity of HPV-OPC prediction. We examined HPV16 E6, E7, E1, and E2 seropositivity and antibody levels in a cohort of older men who have sex with men (MSM).

The Study of Prevention of Anal Cancer (SPANC) was a cohort study of MSM 35 years and older in Sydney, Australia, investigating the natural history of anal HPV and associated diseases.⁵ Men were enrolled from 2010 to 2015. At baseline and 3 annual follow-up visits, anal swabs were taken for cytology and anal HPV DNA detection, and high-resolution anoscopy was performed to detect anal squamous intraepithelial lesions. A blood sample was taken for testing by multiplex HPV serology.⁶ Men who were HPV16 E6 seropositive at baseline had samples from all study visits tested and were contacted for clinical follow-up. The SPANC study had ethics approval from St Vincent’s Hospital, Sydney, Australia (HREC/09/SVH/168), and all study participants provided written consent. Additional approval was obtained to recontact the men with positive baseline serology.

A total of 617 men were enrolled (220 [35.7%] HIV-positive; median age, 49 years), and 603 men had serology results. Of these, 13 had HPV16 E6 antibodies at baseline. One man was HIV positive. One man had antibodies to all 4 HPV16 early antigens (ID1), and 2 men had additional antibodies to HPV16 E2 or E7 (ID2 and ID3). These 3 men were among the 4 with the highest HPV16 E6 antibody levels (Table).

Study participant ID1 died in 2014. He was diagnosed with tonsillar cancer in 2012, enrolled in SPANC in 2013, and was diagnosed with metastatic lung cancer (from his primary tonsillar cancer) in 2014. The remaining 12 individuals were invited for a head and neck examination and a positron emission tomography/computed tomography scan. A total of 9 men consented; 1 refused and 2 were lost to follow-up. One man (ID2) was diagnosed with asymptomatic p16-positive base-of-tongue cancer (T1 N1) and was treated with transoral robotic oropharyngectomy and neck dissection. The other 7 had no symptoms, except 1 participant with a history of throat clearing and recurrent generalized sore throats (ID4). All individuals were scheduled for follow-up visits every 6 months and annual positron emission tomography/computed tomography to account for the diagnostic lead time of HPV16 E6 serology.

This case series informs the feasibility of HPV-OPC screening using HPV serology. Based on published estimates, approximately 1 in 10 seropositive men of this age group will present with HPV-OPC within 10 years,^3,4 which is consistent with the present findings. These results also suggest that incorporating additional early antibodies, antibody levels, and age in screening algorithms may improve the utility of HPV serology for OPC prediction. The main limitation of the present study is its small sample size, and the results require replication in well-designed and sufficiently powered studies.

To our knowledge, this is the first report of a prospectively identified early HPV-OPC case by HPV serology. The early diagnosis of a clinically inapparent, small tumor will almost certainly be highly beneficial for this patient’s long-term survival. Human papillomavirus serology, as a tool to identify a population at the highest risk for development of HPV-OPC, warrants further evaluation.

Corresponding Author: Tim Waterboer, PhD, MSc, Infections and Cancer Epidemiology Division, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany (t.waterboer@dkfz.de).

Published Online: October 1, 2020. doi:10.1001/jamaoncol.2020.4527

Author Contributions: Drs Waterboer and Poynten had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Waterboer, Jin, Grulich, Poynten.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Waterboer, Poynten.

Critical revision of the manuscript for important intellectual content: Brenner, Gallagher, Hillman, Jin, Grulich, Poynten.

Statistical analysis: Waterboer, Brenner, Jin.

Obtained funding: Jin, Grulich.

Administrative, technical, or material support: Gallagher, Grulich, Poynten.

Supervision: Waterboer, Hillman, Grulich.

Conflict of Interest Disclosures: Dr Waterboer serves on advisory boards for Merck Sharp & Dohme. Dr Poynten has received travel funding from Seqiris. Dr Jin reported grants from the Australian National Health and Medical Research Council and grants from Cancer Council New South Wales during the conduct of the study. Dr Grulich has received honoraria and research funding from CSL Biotherapies and honoraria and travel funding from Merck Sharp & Dohme. Dr Hillman has received support from CSL Biotherapies and Merck Sharp & Dohme. No other disclosures were reported.

Funding/Support: This work was supported by the National Health and Medical Research Council Program Grant (568971); and a Cancer Council New South Wales Strategic Research Partnership Program Grant (13–11). Cytological testing materials were provided by Hologic (Australia) Pty Ltd.

Role of the Funder/Sponsor: The National Health and Medical Research Council and the Cancer Council New South Wales Strategic Research Partnership had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The Kirby Institute is affiliated with the Faculty of Medicine, University of New South Wales, and funded by the Australian Government of Health and Ageing. The views expressed in this publication do not necessarily represent the position of the Australian Government.

Additional Contributions: The authors would like to acknowledge the Study of Prevention of Anal Cancer (SPANC) team and St Vincent’s Centre for Applied Medical Research Clinical Trials & Biorepository Team for their contribution to the study. In addition, the authors would like to acknowledge the contributions of Dr Alyssa Cornall, PhD (Women’s Centre for Infectious Disease, Royal Women’s Hospital and the Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, Australia), who performed human papillomavirus testing, and Dr Jennifer Roberts, MBBS (Douglass Hanly Moir Pathology, New South Wales, Australia), who was responsible for the cytological and histological assessments in the SPANC study. Both reviewed and commented on the article. Neither was compensated for their work.