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THE BIOLOGY OF HPV+ CANCER

Engineered

into a Blood Test.

Consensus Recommendations

Full Article:

Evolving Use of Circulating Tumor DNA for HPV+ Oropharyngeal Carcinoma: Consensus Recommendations From the California Head and Neck Consortium

Ho, A.S.; Moyers, J.T.; Attarian, S.; Banker, R.; Birkeland, A.; Chen, M.M.; Coffey, C.S.; Guo, T.; Haidar, Y.; Harris, J.P.; et al. JCO Oncol Pract 2025, 0, OP-25-00450, http://www.doi.org/10.1200/OP-25-00450

December 04, 2025

Pocket Guide:

Consensus Recommendations From the

California Head and Neck Consortium

In December 2025, the California Head and Neck Consortium (CHNC) published the first formal expert consensus recommendations on the clinical use of ctHPVDNA testing for HPV+ oropharyngeal squamous cell carcinoma in the Journal of Clinical Oncology Oncology Practice.11 The consensus was developed using a hybrid Delphi methodology across 33 experts from 15 institutions.

Download our summary of the most impactful recommendations from the paper→

References

  1. Ferrandino RN, Chen S, Kappauf C, et al. Performance of liquid biopsy for diagnosis and surveillance of human papillomavirus–associated oropharyngeal cancer. JAMA Otolaryngol Head Neck Surg. 2023. http://doi.org/10.1001/jamaoto.2023.1937. 
  2. Hanna GJ, Roof SA, Jabalee J, et al. Negative predictive value of circulating tumor tissue modified viral (TTMV)-HPV DNA for HPV-driven oropharyngeal cancer surveillance. Clin Cancer Res. 2023. http://doi.org/10.1158/1078-0432.CCR-23-1478. 
  3. Berger BM, Hanna GJ, et al. Detection of occult recurrence using circulating tumor tissue modified viral HPV DNA among patients treated for HPV-driven oropharyngeal carcinoma. Clin Cancer Res. 2022. http://doi.org/10.1158/1078-0432.CCR-22-0562. 
  4. Kabarriti R, Lloyd S, Jabalee J, et al. Evaluating tumor tissue modified viral (TTMV)-HPV DNA for the early detection of anal squamous cell carcinoma recurrence. Cancers. 2025. http://doi.org/10.3390/cancers17020174. 
  5. Kabarriti R, Lloyd S, Jabalee J, et al. Resolving clinically indeterminate findings during anal cancer surveillance with TTMV-HPV DNA. Cancers. 2026. http://doi.org/10.3390/cancers18010035. 
  6. Chera BS, Kumar S, Shen C, et al. Plasma circulating tumor HPV DNA for the surveillance of cancer recurrence in HPV-associated oropharyngeal cancer. J Clin Oncol. 2020. http://doi.org/10.1200/JCO.19.02444. 
  7. Chera BS, Kumar S, Beaty BT, et al. Rapid clearance profile of plasma circulating tumor HPV type 16 DNA during chemoradiotherapy correlates with disease control in HPV-associated oropharyngeal cancer. Clin Cancer Res. 2019. https://doi.org/10.1158/1078-0432.CCR-19-0211. 
  8. Rettig EM, Schoenfeld JD, Miller J, et al. A prospective trial of biomarker-guided surveillance for HPV-positive oropharynx cancer using plasma tumor tissue–modified viral HPV DNA. Clinical Cancer Research. 2025. http://doi.org/10.1158/1078-0432.CCR-24-3053. 
  9. Mijares K, Ferrandino R, Chai R, et al. Circulating tumor HPV DNA in patients with head and neck carcinoma: Correlation with HPV genotyping. Am J Surg Pathol. 2024.  http://doi.org/10.1097/PAS.0000000000002134. 
  10. Naveris data on file.  
  11. Ho AS, Moyers JT, et al. Evolving use of circulating tumor DNA for HPV+ oropharyngeal carcinoma: Consensus recommendations from the California Head and Neck Consortium. JCO Oncol Pract. 2025. http://doi.org/10.1200/OP-25-00450. 
  12. Surveillance Research Program, National Cancer Institute. SEER*Explorer: An interactive website for SEER cancer statistics [Internet]. 2024.
  13. Kim JK, Tam M, et al. A phase 2 exploratory trial evaluating computed tomography-based midtreatment nodal response to select for de-escalated chemoradiation therapy in the definitive management of p16+ oropharyngeal cancer. Int J Radiat Oncol Biol Phys. 2026. http://doi.org/10.1016/j.ijrobp.2025.09.054.   
  14. Ferrandino RM, Barlow J, Gold B, et al. Diagnostic accuracy of circulating tumor HPV DNA testing in patients with a lateral neck mass. JAMA Otolaryngol Head Neck Surg.2024. http://doi.org/10.1001/jamaoto.2024.2702. 
  15. Papazian MR, Hicks MD, Mannion K, Turner M, and Topf MC. Diagnostic accuracy of HPV circulating tumor DNA following non-diagnostic FNA of a cystic lateral neck mass. Head Neck. 2026. http://doi.org/10.1002/hed.70060.  
  16. Lambert T, Tasoulas J, Flores M, Sheth S, and Patel S. Circulating tumor HPV DNA as an alternative method to determine HPV status in oropharyngeal squamous cell carcinoma. Oral Oncol. 2023. http://doi.org/10.1016/j.oraloncology.2023.106361. 
  17. Elaldi R, Roussel L-M, Gal J, et al. Correlations between long-term quality of life and patient needs and concerns following head and neck cancer treatment and the impact of psychological distress. A multicentric cross-sectional study. Eur Arch Otorhinolaryngol. 2021. http://doi.org/10.1007/s00405-020-06326-8. 
  18. HPV infection. Mayo Clinic. Updated September 2025. https://www.mayoclinic.org/diseases-conditions/hpv-infection/symptoms-causes/syc-20351596.  
  19. Chen Z, Schiffman M, Herrero R, et al. Classification and evolution of human papillomavirus genome variants: Alpha-5 (HPV26, 51, 69, 82), Alpha-6 (HPV30, 53, 56, 66), Alpha-11 (HPV34, 73), Alpha-13 (HPV54) and Alpha-3 (HPV61). Virology. 2018. http://doi.org/10.1016/j.virol.2018.01.002. 
  20. Division of STD Prevention, CDC. Genital HPV infection fact sheet. https://www.cdc.gov/sti/about/about-genital-hpv-infection.html.  
  21. Human papillomaviruses. IARC Monographs. 2012;100B:255-313.
  22. American Cancer Society. HPV and cancer. Updated March 2026. https://www.cancer.org/cancer/cancer-causes/infectious-agents/hpv/hpv-and-cancer-info.html. 
  23. Martin, L. Oral HPV and cancer. WebMD. Updated February 2026. https://www.webmd.com/oral-health/guide/oral-hpv-cancer. 
  24. American Cancer Society. Pap Test (Pap Smear). Updated December 2025. https://www.cancer.org/cancer/cervical-cancer/detection-diagnosis-staging/screening-tests/pap-test.html
  25. Chaturvedi AK, et al. Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers. J Clin Oncol. 2013. http://doi.org/10.1200/JCO.2013.50.3870. 
  26. Kostareli E, Holzinger D, and Hess J. New concepts for translational head and neck oncology: Lessons from HPV-related oropharyngeal squamous cell carcinomas. Front Oncol. 2012. http://doi.org/10.3389/fonc.2012.00036. 
  27. Cancer Research UK. Changes in your appearance due to mouth and oropharyngeal cancer. Updated September 2024. https://www.cancerresearchuk.org/about-cancer/mouth-cancer/living-with/changes-your-appearance
  28. Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus–positive head and neck squamous cell carcinoma in a prospective clinical trial. JNCI: Journal of the National Cancer Institute. 2008. https://doi.org/10.1093/jnci/djn011. 
  29. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010. https://doi.org/10.1056/NEJMoa0912217. 
  30. Gillison ML, Trotti AM, Harris J, et al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet. 2019. https://doi.org/10.1016/S0140-6736(18)32779-X. 
  31. Fakhry C et al. Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma. J Clin Oncol. 2014. https://doi.org/10.1200/JCO.2014.55.1937
  32. Alemany L, Saunier M, Alvarado-Cabrero I, et al. Human papillomavirus DNA prevalence and type distribution in anal carcinomas worldwide. Int J Cancer. 2015. http://doi.org/10.1002/ijc.28963. 
  33. Eng C, et al. The management and prevention of anal squamous cell carcinoma. Am Soc Clin Oncol Educ Book. 2019. http://doi.org/10.1200/EDBK_237433. 
  34. Barnell GM, Schechter MS. Anal cancer screening and prevention—A new era, limited by access to high-resolution anoscopy. JAMA Netw Open. 2024. http://doi.org/10.1001/jamanetworkopen.2024.0019. 
  35. Rim SH, Saraiya M, Beer L, Tie Y, Yuan X, Weiser J. Access to high-resolution anoscopy among persons with HIV and abnormal anal cytology results. JAMA Netw Open. 2024. http://doi.org/10.1001/jamanetworkopen.2024.0068. 
  36. Rim SH, Beer L, Saraiya M, Tie Y, Yuan X, and Weiser J. Prevalence of anal cytology screening among persons with HIV and lack of access to high-resolution anoscopy at HIV care facilities. J Natl Cancer Inst. 2024. http://doi.org/10.1093/jnci/djae094. 
  37. Ghodraty Jabloo V, Alibhai SMH, Fitch M, Tourangeau AE, Ayala AP, and Puts M. Antecedents and outcomes of uncertainty in older adults with cancer: A scoping review of the literature. Oncol Nurs Forum. 2017. http://doi.org/10.1188/17.ONF.E152-E167. 
  38. Bergerot CD, et al. Fear of cancer recurrence or progression: What is it and what can we do about it? Am Soc Clin Oncol Educ Book. 2022. http://doi.org/10.1200/EDBK_100031. 
  39. Roof SA, Jabalee J, Rettig EM, Chennareddy S, Ferrandino RM, Chen S, Posner MR, Genden EM, Chai RL, Sims J, Thrash E, Stern SJ, Kalman NS, Yarlagadda S, Raben A, Clements L, Mendelsohn A, Kaczmar JM, Pandey Y, Bhayani M, Del Vecchio Fitz C, Hanna GJ. Utility of TTMV-HPV DNA in resolving indeterminate findings during oropharyngeal cancer surveillance. Oral Oncol. 2024. http://doi.org/10.1016/j.oraloncology.2024.106874. 
  40. Hollander A, Nonaka T. Cell-free HPV-DNA as a high-accuracy biomarker for treatment de-escalation in HPV-positive head and neck squamous cell carcinoma. Front Oncol. 2025. http://doi.org/10.3389/fonc.2025.1569877. 
  41. Bastien AJ, Ng J, Cong I, Garcia J, Walgama ES, Luu M, Jang JK, Mita AC, Scher KS, Moyers JT, Mallen-St. Clair J, Maghami E, Chen MM, Zumsteg ZS, and Ho AS. Patient perceptions underlying ctDNA molecular surveillance for HPV(+) oropharyngeal squamous cell carcinoma. Oral Oncol. 2024. https://doi.org/10.1016/j.oraloncology.2024.106894. 
  42. Lin MG, Zhu A, Read PW, Garneau J, and McLaughlin C. Novel HPV associated oropharyngeal squamous cell carcinoma surveillance DNA assay cost analysis. Laryngoscope. 2023. http://doi.org/10.1002/lary.30701. 
  43. Gupta T, Master Z, Kannan S. et al. Diagnostic performance of post-treatment FDG PET or FDG PET/CT imaging in head and neck cancer: A systematic review and meta-analysis. Eur J Nucl Med Mol Imaging. 2011. http://doi.org/10.1007/s00259-011-1893-y. 
  44. Lang Kuhs KA, Brenner JC, Holsinger FC, and Rettig EM. Circulating tumor HPV DNA for surveillance of HPV-positive oropharyngeal squamous cell carcinoma: A narrative review. JAMA Oncol. 2023. http://doi.org/10.1001/jamaoncol.2023.4042. 
  45. Huffman BM, Singh H, Ali LR, Horick N, Wang SJ, Hoffman MT, et al. Biomarkers of pembrolizumab efficacy in advanced anal squamous cell carcinoma: analysis of a phase II clinical trial and a cohort of long-term responders. Journal for ImmunoTherapy of Cancer. 2024. http://doi.org/10.1136/jitc-2023-008436. 
  46. Kais A, Santiago SP, Han PC, Clump DA, Stokes WA, Fancy T, Cui R, Martin E and Turner MT. Human papillomavirus circulating tumor DNA: a diagnostic tool in squamous cell carcinoma of unknown primary-a pilot study. Front Oncol. 2024. http://doi.org/10.3389/fonc.2024.1376595. 
  47. Rettig EM, Wang AA, Tran N, et al. Association of pretreatment circulating tumor tissue-modified viral HPV DNA with clinicopathologic factors in HPV-positive oropharyngeal cancer. JAMA Otolaryngol Head Neck Surg. 2022.  Article: http://doi.org/10.1001/jamaoto.2022.3282.  Erratum: http://doi.org/10.1001/jamaoto.2022.4289. 
  48. Ellsworth G, Shen R, Marcelin K-A, Majumdar R, Bazil M, Moore G, Nelson M, Alland I, Sepulveda G, Wilkin T, and Higginson D. High specificity of HPV cell-free DNA tests in persons with HIV for the detection of HPV-related cancer. J Acquir Immune Defic Syndr. 2023. http://doi.org/10.1097/QAI.0000000000003231. 
  49. Routman DM,  Kumar S, Chera BS, Jethwa KR, Van Abel KM, Frechette K, DeWees T, Golafshar M, Garcia JJ, Price DL, Kasperbauer JL, Patel SH, Neben-Wittich MA, Laack NL, Chintakuntlawar AV, Price KA, Liu MC, Foote RL, Moore EJ, Gupta GP, and Ma DJ. Detectable postoperative circulating tumor human papillomavirus DNA and association with recurrence in patients with HPV-associated oropharyngeal squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2022. http://doi.org/10.1016/j.ijrobp.2022.02.012.   
  50. Huttinger ZM, Gogineni E, Baliga S, Blakaj DM, Bhateja P, Bonomi M, Kang SY, Old MO, Seim NB, VanKoevering KK, Agrawal A, Ozer E, Rocco JW, and Haring CT. Circulating tumor DNA determines induction chemotherapy response in HPV associated oropharyngeal squamous cell carcinoma: A pilot study. Oral Oncol. 2025. http://doi.org/10.1016/j.oraloncology.2025.107179.   
  51. Frazer ML, Yang G, Felder S, McDonald J, Sanchez J, Dessureault S, Imanirad I, Carballido E, Kim R, Hoffe S, and Frakes J. Determining optimal follow-up for patients with anal cancer following chemoradiation. Am J Clin Oncol. 2020. http://doi.org/10.1097/COC.0000000000000673. 
  52. Chung CH, Li J, Steuer CE, Bhateja P, Johnson M, Masannat J, Poole MI, Song F, Hernandez-Prera JC, Molina H, Wenig BM, Kumar S, Kuperwasser C, Stephens PJ, Farinhas JM, Shin DM, Kish JA, Muzaffar J, Kirtane K, Rocco JW, Schell MJ, Saba NF, and Bonomi M. Phase II multi-institutional clinical trial result of concurrent cetuximab and nivolumab in recurrent and/or metastatic head and neck squamous cell carcinoma. Clin Cancer Res. 2022. http://doi.org/10.1158/1078-0432.CCR-21-3849. 
  53. Cabel L, Jeannot E, Bieche I, Vacher S, Callens C, Bazire L, Morel A, Bernard-Tessier A, Chemlali W, Schnitzler A, Lièvre A, Otz J, Minsat M, Vincent-Salomon A, Pierga J-Y, Buecher B, Mariani P, Proudhon C, Bidard F-C, and Cacheux W. Prognostic impact of residual HPV ctDNA detection after chemoradiotherapy for anal squamous cell carcinoma. Clin Cancer Res. 2018. http://doi.org/10.1158/1078-0432.CCR-18-0922. 
  54. Bernard-Tessier A, Jeannot E, Guenat D, Debernardi A, Michel M, Proudhon C, Vincent-Salomon A, Bièche I, Pierga J-Y, Buecher B, Meurisse A, François E, Cohen R, Jary M, Vendrely V, Samalin E, El Hajbi F, Baba-Hamed N, Borg C, Bidard F-C, and Kim S. Clinical validity of HPV circulating tumor DNA in advanced anal carcinoma: An ancillary study to the epitopes-HPV02 trial. Clin Cancer Res. 2019. http://doi.org/10.1158/1078-0432.CCR-18-2984. 
  55. Wong ET, Dmytriw AA, Yu E, et al. 18F-FDG PET/CT for locoregional surveillance following definitive treatment of head and neck cancer: A meta-analysis of reported studies. Head & Neck. 2019. https://doi.org/10.1002/hed.25513
  56. Masroor F, Corpman D, Carpenter DM, Ritterman Weintraub M, Cheung KHN, and Wang KH. Association of NCCN-recommended posttreatment surveillance with outcomes in patients with HPV-associated oropharyngeal squamous cell carcinoma. JAMA Otolaryngol. Neck Surg. 2019. https://doi.org/10.1001/jamaoto.2019.1934.   
  57. Su W, Rajeev-Kumar G, Kang M, et al. Long-term outcomes in patients with recurrent human papillomavirus-positive oropharyngeal cancer after upfront transoral robotic surgery. Head & Neck. 2020. https://doi.org/10.1002/hed.26396
  58. Gimenez F, Costa-e-Silva IT, Daumas A,  Araújo, Jd, Medeiros SG, and Ferreira, L. The value of high-resolution anoscopy in the diagnosis of anal cancer precursor lesions in HIV-positive patients. Arq. Gastroenterol. 2011. https://doi.org/10.1590/S0004-28032011000200010
  59. Brenes D, Kortum A, Carns J, Mutetwa T, Schwarz R, Liu Y, Sigel K, Richards-Kortum R, Anandasabapathy S, Gaisa M, and Chiao, E. Automated in vivo high-resolution imaging to detect human papillomavirus–associated anal precancer in persons living with HIV. Clinical and Translational Gastroenterology. 2023. http://doi.org/10.14309/ctg.0000000000000558
  60. Ang CW, Dawson R, Hall C, and Farmer M. The diagnostic value of digital rectal examination in primary care for palpable rectal tumour. Colorectal Disease. 2008. https://doi.org/10.1111/j.1463-1318.2007.01381.x
  61. Adusumilli P, Elsayed N, Theophanous S, Samuel R, Cooper R, Casanova N, Tolan DJ, Gilbert A, and Scarsbrook AF. Combined PET-CT and MRI for response evaluation in patients with squamous cell anal carcinoma treated with curative-intent chemoradiotherapy. Eur Radiol.  2022. http://doi.org/10.1007/s00330-022-08648-z.  
  62. Eng C, Ciombor KK, Cho M, Dorth JA, Rajdev LN, Horowitz DP, Gollub MJ, Jácome AA, Lockney NA, Muldoon RL, Washington MK, O’Brian BA, Benny A, Lebeck Lee CM, Benson AB 3rd, Goodman KA, and Morris VK. Anal cancer: Emerging standards in a rare disease. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2022. http://doi.org/10.1200/JCO.21.02566. 
  63. Littlejohn JB, and Brister KA. Management of Recurrent Anal Cancer. Oncol. Clin. 2025. https://pubmed.ncbi.nlm.nih.gov/39547772/
  64. Upadhyay L, Hartzell M, Parikh AR, Strickland MR, Klempner S, and Malla M. Recent advances in the management of anal cancer. Healthcare. 2023. https://doi.org/10.3390/healthcare11233010