Diagnostic accuracy of HPV16 early antigen serology for HPV-driven oropharyngeal cancer is independent of age and sex

Johannes M.A. Kusters; Brenda Diergaarde; Andrew Ness; Maarten F. Schim van der Loeff; Janneke C.M. Heijne; Lea Schroeder; Katrina Hueniken; James D. McKay; Gary J. Macfarlane; Pagona Lagiou; Areti Lagiou; Jerry Polesel; Antonio Agudo; Laia Alemany; Wolfgang Ahrens; Claire M. Healy; David I. Conway; Max Robinson; Christina Canova; Ivana Holcátová; Lorenzo Richiardi; Ariana Znaor; Miranda Pring; Steve Thomas; D. Neil Hayes; Geoffrey Liu; Rayjean J. Hung; Paul Brennan; Andrew F. Olshan; Shama Virani; Tim Waterboer

doi:10.1002/ijc.34710

Diagnostic accuracy of HPV16 early antigen serology for HPV-driven oropharyngeal cancer is independent of age and sex

Johannes M.A. Kusters, Brenda Diergaarde, Andrew Ness, Maarten F. Schim van der Loeff, Janneke C.M. Heijne, Lea Schroeder, Katrina Hueniken, James D. McKay, Gary J. Macfarlane, Pagona Lagiou, Areti Lagiou, Jerry Polesel, Antonio Agudo, Laia Alemany, Wolfgang Ahrens, Claire M. Healy, David I. Conway, Max Robinson, Christina Canova, Ivana HolcátováLorenzo Richiardi, Ariana Znaor, Miranda Pring, Steve Thomas, D. Neil Hayes, Geoffrey Liu, Rayjean J. Hung, Paul Brennan, Andrew F. Olshan, Shama Virani, Tim Waterboer^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

4 Citations (Scopus)

Abstract

A growing proportion of head and neck cancer (HNC), especially oropharyngeal cancer (OPC), is caused by human papillomavirus (HPV). There are several markers for HPV-driven HNC, one being HPV early antigen serology. We aimed to investigate the diagnostic accuracy of HPV serology and its performance across patient characteristics. Data from the VOYAGER consortium was used, which comprises five studies on HNC from North America and Europe. Diagnostic accuracy, that is, sensitivity, specificity, Cohen's kappa and correctly classified proportions of HPV16 E6 serology, was assessed for OPC and other HNC using p16^INK4a immunohistochemistry (p16), HPV in situ hybridization (ISH) and HPV PCR as reference methods. Stratified analyses were performed for variables including age, sex, smoking and alcohol use, to test the robustness of diagnostic accuracy. A risk-factor analysis based on serology was conducted, comparing HPV-driven to non-HPV-driven OPC. Overall, HPV serology had a sensitivity of 86.8% (95% CI 85.1-88.3) and specificity of 91.2% (95% CI 88.6-93.4) for HPV-driven OPC using p16 as a reference method. In stratified analyses, diagnostic accuracy remained consistent across sex and different age groups. Sensitivity was lower for heavy smokers (77.7%), OPC without lymph node involvement (74.4%) and the ARCAGE study (66.7%), while specificity decreased for cases with <10 pack-years (72.1%). The risk-factor model included study, year of diagnosis, age, sex, BMI, alcohol use, pack-years, TNM-T and TNM-N stage. HPV serology is a robust biomarker for HPV-driven OPC, and its diagnostic accuracy is independent of age and sex. Future research is suggested on the influence of smoking on HPV antibody levels.

Original language	English
Pages (from-to)	389-402
Number of pages	14
Journal	International Journal of Cancer
Volume	154
Issue number	2
Early online date	11 Sept 2023
DOIs	https://doi.org/10.1002/ijc.34710 https://doi.org/10.1002/ijc.34710
Publication status	Published - 11 Sept 2023

Bibliographical note

Funding Information:
This project was funded in part by NIH/NIDCR R01 DE025712 (Paul Brennan, Brenda Diergaarde and Neil Hayes). The Alcohol‐Related Cancers and Genetic Susceptibility Study in Europe (ARCAGE) was funded by the European Commission's fifth framework program (QLK1‐2001‐00182), the Italian Association for Cancer Research, Compagnia di San Paolo/FIRMS, Region Piemonte and Padova University (CPDA057222). We thank Dr. Wolfgang Ahrens, PhD (Universität Bremen, Germany) for his support in ARCAGE study. The Carolina Head and Neck Cancer Epidemiology (CHANCE) study was supported in part by the National Cancer Institute (R01‐CA90731). The Head and Neck 5000 study was a component of independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP‐PG‐0707‐10034). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Core funding was also provided through awards from Above and Beyond, University Hospitals Bristol and Weston Research Capability Funding and the NIHR Senior Investigator award to Professor Andy Ness. Human papillomavirus (HPV) serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant number: C18281/A19169). The University of Pittsburgh head and neck cancer case‐control study is supported by US National Institutes of Health grants P50CA097190 and P30CA047904. The MSH‐PMH study was supported by the Canadian Cancer Society Research Institute and the Lusi Wong Programs at the Princess Margaret Hospital Foundation.

Publisher Copyright:
© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

Keywords

diagnostic accuracy
head and neck cancer
human papillomavirus
oropharyngeal cancer
serology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Kusters, J. M. A., Diergaarde, B., Ness, A., Schim van der Loeff, M. F., Heijne, J. C. M., Schroeder, L., Hueniken, K., McKay, J. D., Macfarlane, G. J., Lagiou, P., Lagiou, A., Polesel, J., Agudo, A., Alemany, L., Ahrens, W., Healy, C. M., Conway, D. I., Robinson, M., Canova, C., ... Waterboer, T. (2023). Diagnostic accuracy of HPV16 early antigen serology for HPV-driven oropharyngeal cancer is independent of age and sex. International Journal of Cancer, 154(2), 389-402. https://doi.org/10.1002/ijc.34710, https://doi.org/10.1002/ijc.34710

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title = "Diagnostic accuracy of HPV16 early antigen serology for HPV-driven oropharyngeal cancer is independent of age and sex",

abstract = "A growing proportion of head and neck cancer (HNC), especially oropharyngeal cancer (OPC), is caused by human papillomavirus (HPV). There are several markers for HPV-driven HNC, one being HPV early antigen serology. We aimed to investigate the diagnostic accuracy of HPV serology and its performance across patient characteristics. Data from the VOYAGER consortium was used, which comprises five studies on HNC from North America and Europe. Diagnostic accuracy, that is, sensitivity, specificity, Cohen's kappa and correctly classified proportions of HPV16 E6 serology, was assessed for OPC and other HNC using p16INK4a immunohistochemistry (p16), HPV in situ hybridization (ISH) and HPV PCR as reference methods. Stratified analyses were performed for variables including age, sex, smoking and alcohol use, to test the robustness of diagnostic accuracy. A risk-factor analysis based on serology was conducted, comparing HPV-driven to non-HPV-driven OPC. Overall, HPV serology had a sensitivity of 86.8\% (95\% CI 85.1-88.3) and specificity of 91.2\% (95\% CI 88.6-93.4) for HPV-driven OPC using p16 as a reference method. In stratified analyses, diagnostic accuracy remained consistent across sex and different age groups. Sensitivity was lower for heavy smokers (77.7\%), OPC without lymph node involvement (74.4\%) and the ARCAGE study (66.7\%), while specificity decreased for cases with <10 pack-years (72.1\%). The risk-factor model included study, year of diagnosis, age, sex, BMI, alcohol use, pack-years, TNM-T and TNM-N stage. HPV serology is a robust biomarker for HPV-driven OPC, and its diagnostic accuracy is independent of age and sex. Future research is suggested on the influence of smoking on HPV antibody levels.",

keywords = "diagnostic accuracy, head and neck cancer, human papillomavirus, oropharyngeal cancer, serology",

author = "Kusters, \{Johannes M.A.\} and Brenda Diergaarde and Andrew Ness and \{Schim van der Loeff\}, \{Maarten F.\} and Heijne, \{Janneke C.M.\} and Lea Schroeder and Katrina Hueniken and McKay, \{James D.\} and Macfarlane, \{Gary J.\} and Pagona Lagiou and Areti Lagiou and Jerry Polesel and Antonio Agudo and Laia Alemany and Wolfgang Ahrens and Healy, \{Claire M.\} and Conway, \{David I.\} and Max Robinson and Christina Canova and Ivana Holc{\'a}tov{\'a} and Lorenzo Richiardi and Ariana Znaor and Miranda Pring and Steve Thomas and Hayes, \{D. Neil\} and Geoffrey Liu and Hung, \{Rayjean J.\} and Paul Brennan and Olshan, \{Andrew F.\} and Shama Virani and Tim Waterboer",

note = "Funding Information: This project was funded in part by NIH/NIDCR R01 DE025712 (Paul Brennan, Brenda Diergaarde and Neil Hayes). The Alcohol‐Related Cancers and Genetic Susceptibility Study in Europe (ARCAGE) was funded by the European Commission's fifth framework program (QLK1‐2001‐00182), the Italian Association for Cancer Research, Compagnia di San Paolo/FIRMS, Region Piemonte and Padova University (CPDA057222). We thank Dr. Wolfgang Ahrens, PhD (Universit{\"a}t Bremen, Germany) for his support in ARCAGE study. The Carolina Head and Neck Cancer Epidemiology (CHANCE) study was supported in part by the National Cancer Institute (R01‐CA90731). The Head and Neck 5000 study was a component of independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP‐PG‐0707‐10034). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Core funding was also provided through awards from Above and Beyond, University Hospitals Bristol and Weston Research Capability Funding and the NIHR Senior Investigator award to Professor Andy Ness. Human papillomavirus (HPV) serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant number: C18281/A19169). The University of Pittsburgh head and neck cancer case‐control study is supported by US National Institutes of Health grants P50CA097190 and P30CA047904. The MSH‐PMH study was supported by the Canadian Cancer Society Research Institute and the Lusi Wong Programs at the Princess Margaret Hospital Foundation. Publisher Copyright: {\textcopyright} 2023 The Authors. International Journal of Cancer published by John Wiley \& Sons Ltd on behalf of UICC.",

year = "2023",

month = sep,

day = "11",

doi = "10.1002/ijc.34710",

language = "English",

volume = "154",

pages = "389--402",

journal = "International Journal of Cancer",

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Kusters, JMA, Diergaarde, B, Ness, A, Schim van der Loeff, MF, Heijne, JCM, Schroeder, L, Hueniken, K, McKay, JD, Macfarlane, GJ, Lagiou, P, Lagiou, A, Polesel, J, Agudo, A, Alemany, L, Ahrens, W, Healy, CM, Conway, DI, Robinson, M, Canova, C, Holcátová, I, Richiardi, L, Znaor, A, Pring, M, Thomas, S, Hayes, DN, Liu, G, Hung, RJ, Brennan, P, Olshan, AF, Virani, S & Waterboer, T 2023, 'Diagnostic accuracy of HPV16 early antigen serology for HPV-driven oropharyngeal cancer is independent of age and sex', International Journal of Cancer, vol. 154, no. 2, pp. 389-402. https://doi.org/10.1002/ijc.34710, https://doi.org/10.1002/ijc.34710

TY - JOUR

T1 - Diagnostic accuracy of HPV16 early antigen serology for HPV-driven oropharyngeal cancer is independent of age and sex

AU - Kusters, Johannes M.A.

AU - Diergaarde, Brenda

AU - Ness, Andrew

AU - Schim van der Loeff, Maarten F.

AU - Heijne, Janneke C.M.

AU - Schroeder, Lea

AU - Hueniken, Katrina

AU - McKay, James D.

AU - Macfarlane, Gary J.

AU - Lagiou, Pagona

AU - Lagiou, Areti

AU - Polesel, Jerry

AU - Agudo, Antonio

AU - Alemany, Laia

AU - Ahrens, Wolfgang

AU - Healy, Claire M.

AU - Conway, David I.

AU - Robinson, Max

AU - Canova, Christina

AU - Holcátová, Ivana

AU - Richiardi, Lorenzo

AU - Znaor, Ariana

AU - Pring, Miranda

AU - Thomas, Steve

AU - Hayes, D. Neil

AU - Liu, Geoffrey

AU - Hung, Rayjean J.

AU - Brennan, Paul

AU - Olshan, Andrew F.

AU - Virani, Shama

AU - Waterboer, Tim

N1 - Funding Information: This project was funded in part by NIH/NIDCR R01 DE025712 (Paul Brennan, Brenda Diergaarde and Neil Hayes). The Alcohol‐Related Cancers and Genetic Susceptibility Study in Europe (ARCAGE) was funded by the European Commission's fifth framework program (QLK1‐2001‐00182), the Italian Association for Cancer Research, Compagnia di San Paolo/FIRMS, Region Piemonte and Padova University (CPDA057222). We thank Dr. Wolfgang Ahrens, PhD (Universität Bremen, Germany) for his support in ARCAGE study. The Carolina Head and Neck Cancer Epidemiology (CHANCE) study was supported in part by the National Cancer Institute (R01‐CA90731). The Head and Neck 5000 study was a component of independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP‐PG‐0707‐10034). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Core funding was also provided through awards from Above and Beyond, University Hospitals Bristol and Weston Research Capability Funding and the NIHR Senior Investigator award to Professor Andy Ness. Human papillomavirus (HPV) serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant number: C18281/A19169). The University of Pittsburgh head and neck cancer case‐control study is supported by US National Institutes of Health grants P50CA097190 and P30CA047904. The MSH‐PMH study was supported by the Canadian Cancer Society Research Institute and the Lusi Wong Programs at the Princess Margaret Hospital Foundation. Publisher Copyright: © 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

PY - 2023/9/11

Y1 - 2023/9/11

N2 - A growing proportion of head and neck cancer (HNC), especially oropharyngeal cancer (OPC), is caused by human papillomavirus (HPV). There are several markers for HPV-driven HNC, one being HPV early antigen serology. We aimed to investigate the diagnostic accuracy of HPV serology and its performance across patient characteristics. Data from the VOYAGER consortium was used, which comprises five studies on HNC from North America and Europe. Diagnostic accuracy, that is, sensitivity, specificity, Cohen's kappa and correctly classified proportions of HPV16 E6 serology, was assessed for OPC and other HNC using p16INK4a immunohistochemistry (p16), HPV in situ hybridization (ISH) and HPV PCR as reference methods. Stratified analyses were performed for variables including age, sex, smoking and alcohol use, to test the robustness of diagnostic accuracy. A risk-factor analysis based on serology was conducted, comparing HPV-driven to non-HPV-driven OPC. Overall, HPV serology had a sensitivity of 86.8% (95% CI 85.1-88.3) and specificity of 91.2% (95% CI 88.6-93.4) for HPV-driven OPC using p16 as a reference method. In stratified analyses, diagnostic accuracy remained consistent across sex and different age groups. Sensitivity was lower for heavy smokers (77.7%), OPC without lymph node involvement (74.4%) and the ARCAGE study (66.7%), while specificity decreased for cases with <10 pack-years (72.1%). The risk-factor model included study, year of diagnosis, age, sex, BMI, alcohol use, pack-years, TNM-T and TNM-N stage. HPV serology is a robust biomarker for HPV-driven OPC, and its diagnostic accuracy is independent of age and sex. Future research is suggested on the influence of smoking on HPV antibody levels.

AB - A growing proportion of head and neck cancer (HNC), especially oropharyngeal cancer (OPC), is caused by human papillomavirus (HPV). There are several markers for HPV-driven HNC, one being HPV early antigen serology. We aimed to investigate the diagnostic accuracy of HPV serology and its performance across patient characteristics. Data from the VOYAGER consortium was used, which comprises five studies on HNC from North America and Europe. Diagnostic accuracy, that is, sensitivity, specificity, Cohen's kappa and correctly classified proportions of HPV16 E6 serology, was assessed for OPC and other HNC using p16INK4a immunohistochemistry (p16), HPV in situ hybridization (ISH) and HPV PCR as reference methods. Stratified analyses were performed for variables including age, sex, smoking and alcohol use, to test the robustness of diagnostic accuracy. A risk-factor analysis based on serology was conducted, comparing HPV-driven to non-HPV-driven OPC. Overall, HPV serology had a sensitivity of 86.8% (95% CI 85.1-88.3) and specificity of 91.2% (95% CI 88.6-93.4) for HPV-driven OPC using p16 as a reference method. In stratified analyses, diagnostic accuracy remained consistent across sex and different age groups. Sensitivity was lower for heavy smokers (77.7%), OPC without lymph node involvement (74.4%) and the ARCAGE study (66.7%), while specificity decreased for cases with <10 pack-years (72.1%). The risk-factor model included study, year of diagnosis, age, sex, BMI, alcohol use, pack-years, TNM-T and TNM-N stage. HPV serology is a robust biomarker for HPV-driven OPC, and its diagnostic accuracy is independent of age and sex. Future research is suggested on the influence of smoking on HPV antibody levels.

KW - diagnostic accuracy

KW - head and neck cancer

KW - human papillomavirus

KW - oropharyngeal cancer

KW - serology

UR - http://www.scopus.com/inward/record.url?scp=85170574338&partnerID=8YFLogxK

U2 - 10.1002/ijc.34710

DO - 10.1002/ijc.34710

M3 - Article (Academic Journal)

C2 - 37694289

AN - SCOPUS:85170574338

SN - 0020-7136

VL - 154

SP - 389

EP - 402

JO - International Journal of Cancer

JF - International Journal of Cancer

IS - 2

ER -

Diagnostic accuracy of HPV16 early antigen serology for HPV-driven oropharyngeal cancer is independent of age and sex

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Bibliographical note

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