Surveillance and Monitoring Techniques for HPV-Related Head and Neck Squamous Cell Carcinoma: Circulating Tumor DNA

Opinion statement

Human papilloma virus (HPV) related head and neck cancer is rising in prevalence, preferentially affecting young patients and imparting long term toxicities. Despite this, there are no screening tests or clinical biomarkers for treatment monitoring. HPV circulating tumor DNA (HPV ctDNA) represents a novel circulating biomarker which may provide real-time assessment of tumor response to therapy and recurrence. Early work suggests the promise of this assay as a predictive biomarker in numerous clinical settings, namely risk of recurrence after chemoradiation in locally advanced disease. Advancement of these findings to the clinic will require a collaborative effort in the field, including technical harmonization of assay testing characteristics, understanding of the normal kinetics in patients being treated with standard of care therapies, and appropriately designed phase III trials prior to implementation in the clinic. If successful, HPV ctDNA has the potential to revolutionize clinical trial treatment paradigms and transform patient care.

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References and recommended Reading

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1

    Mourad M, Jetmore T, Jategaonkar AA, Moubayed S, Moshier E, Urken ML. Epidemiological trends of head and neck Cancer in the United States: a SEER population study. J Oral Maxillofac Surg. 2017;75(12):2562–72. Epub 2017 May 22. https://doi.org/10.1016/j.joms.2017.05.008.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29(32):4294–301. https://doi.org/10.1200/JCO.2011.36.4596.

  3. 3

    Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24–35. https://doi.org/10.1056/NEJMoa0912217.

  4. 4

    Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100:261–9. https://doi.org/10.1093/jnci/djn011.

  5. 5

    Mirghani H, Lang Kuhs KA, Waterboer T. Biomarkers for early identification of recurrences in HPV-driven oropharyngeal cancer. Oral Oncol. 2018 Jul;82:108–14. https://doi.org/10.1016/j.oraloncology.2018.05.015 Epub 2018 May 21.

  6. 6

    Jayaram SC, Muzaffar SJ, Ahmed I, Dhanda J, Paleri V, Mehanna H. Efficacy, outcomes, and complication rates of different surgical and nonsurgical treatment modalities for recurrent/residual oropharyngeal carcinoma: a systematic review and meta-analysis. Head Neck. 2016;38:1855–61. https://doi.org/10.1002/hed.24531.

  7. 7

    National Comprehensive Cancer Network. Cancer of the Oropharynx (p16 [HPV]-positive) (Version 1.2018). https://oncolife.com.ua/doc/nccn/Head_and_Neck_Cancers.pdf. .

  8. 8

    Viens LJ, Henley SJ, Watson M, Markowitz LE, Thomas CC, Thompson TD, et al. Centers for Disease Control and Prevention (CDC). Human papillomavirus–associated cancers—United States, 2008–2012. MMWR. 2016;65(26):661–6.

  9. 9

    Tota JE, Best AF, Zumsteg ZS, Gillison ML, Rosenberg PS, Chaturvedi AK. Evolution of the oropharynx Cancer epidemic in the United States: moderation of increasing incidence in younger individuals and shift in the burden to older individuals. J Clin Oncol. 2019;37(18):1538–46. https://doi.org/10.1200/JCO.19.00370.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    De Mattos-Arruda L, Cortes J, Santarpia L, Vivancos A, Tabernero J, Reis-Filho JS, et al. Circulating tumour cells and cell-free DNA as tools for managing breast cancer. Nat Rev Clin Oncol. 2013;10:377–89. https://doi.org/10.1038/nrclinonc.2013.80.

    CAS  Article  PubMed  Google Scholar 

  11. 11

    Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368:1199–209. https://doi.org/10.1056/NEJMoa1213261.

    CAS  Article  Google Scholar 

  12. 12

    De Maio G, Rengucci C, Zoli W, Calistri D. Circulating and stool nucleic acid analysis for colorectal cancer diagnosis. World J Gastroenterol. 2014;20:957–67. https://doi.org/10.3748/wjg.v20.i4.957.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Smerage JB, Barlow WE, Hortobagyi GN, Winer EP, Leyland-Jones B, Srkalovic G, et al. Circulating tumor cells and response to chemotherapy in metastatic breast Cancer: SWOG S0500. J Clin Oncol. 2014;32(31):3483–9. https://doi.org/10.1200/JCO.2014.56.2561.

  14. 14

    Jensen KK, Gronhoj C, Jensen DH, von Buchwald C. Circulating human papillomavirus DNA as a surveillance tool in head and neck squamous cell carcinoma: a systematic review and meta-analysis. Clin Otolaryngol. 2018;43:1242–9. https://doi.org/10.1111/coa.13136.

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Hanna GJ, Supplee JG, Kuang Y, Mahmood U, Lau CJ, Haddad RI, et al. Plasma HPV cell-free DNA monitoring in advanced HPV-associated oropharyngeal cancer. Ann Oncol. 2018;29:1980–6. https://doi.org/10.1093/annonc/mdy251.

  16. 16

    Harle A, Guillet J, Thomas J, Demange J, Dolivet G, Peiffert D, et al. HPV insertional pattern as a personalized tumor marker for the optimized tumor diagnosis and follow-up of patients with HPV-associated carcinomas: a case report. BMC Cancer. 2019;19:277. https://doi.org/10.1186/s12885-019-5447-1.

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    Egyud M, Sridhar P, Devaiah A, Yamada E, Saunders S, Ståhlberg A, et al. Plasma circulating tumor DNA as a potential tool for disease monitoring in head and neck cancer. Head Neck. 2019;41:1351–8. https://doi.org/10.1002/hed.25563.

  18. 18

    Bellairs JA, Hasina R, Agrawal N. Tumor DNA: an emerging biomarker in head and neck cancer. Cancer Metastasis Rev. 2017;36:515–23. https://doi.org/10.1007/s10555-017-9685-x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Cao H, Banh A, Kwok S, Shi X, Wu S, Krakow T, et al. Quantitation of human papillomavirus DNA in plasma of oropharyngeal carcinoma patients. Int J Radiat Oncol Biol Phys. 2012;82:e351–8. https://doi.org/10.1016/j.ijrobp.2011.05.061.

  20. 20••

    Chera BS, Kumar S, Shen C, Amdur R, Dagan R, Green R, et al. Plasma Circulating Tumor HPV DNA for the Surveillance of Cancer Recurrence in HPV-Associated Oropharyngeal Cancer. J Clin Oncol. 2020;38(10):1050–1058. https://doi.org/10.1200/JCO.19.02444. Epub 2020 Feb 4. Prospective clinical trial of patients with non-metastatic HPV-positive OPSCC demonstrating that detection of HPV ctDNA in two consecutive plasma samples during post-treatment surveillance has high PPV and NPV for identifying disease recurrence.

  21. 21.

    Capone RB, Pai SI, Koch WM, Gillison ML, Danish HN, Westra WH, et al. Detection and quantitation of human papillomavirus (HPV) DNA in the sera of patients with HPV-associated head and neck squamous cell carcinoma. Clin Cancer Res. 2000;6:4171–5.

    CAS  PubMed  Google Scholar 

  22. 22.

    Dahlstrom KR, Li G, Hussey CS, Vo JT, Wei Q, Zhao C, et al. Circulating human papillomavirus DNA as a marker for disease extent and recurrence among patients with oropharyngeal cancer. Cancer. 2015;121(19):3455–64. https://doi.org/10.1002/cncr.29538.

  23. 23.

    Rutkowski TW, Mazurek AM, Śnietura M, Hejduk B, Jędrzejewska M, Bobek-Billewicz B, et al. Circulating HPV16 DNA may complement imaging assessment of early treatment efficacy in patients with HPV-positive oropharyngeal cancer. J Transl Med. 2020;18(1):167. https://doi.org/10.1186/s12967-020-02330-y.

  24. 24.

    Lee JY, Garcia-Murillas I, Cutts RJ, De Castro DG, Grove L, Hurley T, et al. Predicting response to radical (chemo)radiotherapy with circulating HPV DNA in locally advanced head and neck squamous carcinoma. Br J Cancer. 2017;117:876–83. https://doi.org/10.1038/bjc.2017.258.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Tanaka H, Takemoto N, Horie M, Takai E, Fukusumi T, Suzuki M, et al. Circulating tumor HPV DNA complements PET-CT in guiding management after radiotherapy in HPV-related squamous cell carcinoma of the head and neck. Int J Cancer. 2020 Sep 7. https://doi.org/10.1002/ijc.33287.

  26. 26.

    Hanna GJ, Lau CJ, Mahmood U, Supplee JG, Mogili AR, Haddad RI, et al. Salivary HPV DNA informs locoregional disease status in advanced HPV-associated oropharyngeal cancer. Oral Oncol. 2019;95:120–6. https://doi.org/10.1016/j.oraloncology.2019.06.019.

  27. 27.

    Hilke FJ, Muyas F, Admard J, Kootz B, Nann D, Welz S, et al. Dynamics of cell-free tumour DNA correlate with treatment response of head and neck cancer patients receiving radiochemotherapy. Radiother Oncol. 2020;17:S0167-8140(20)30421-7. https://doi.org/10.1016/j.radonc.2020.07.027. Online ahead of print.

  28. 28.

    Xi L, Pham T.H, Payabyab E.C, Sherry R.M, Rosenberg S.A, Raffeld M. Circulating tumor DNA as an early indicator of response to T-cell transfer immunotherapy in metastatic melanoma. Clin Cancer Res 2016;22:5480–5486. https://doi.org/10.1158/1078-0432.CCR-16-0613.

  29. 29.

    Higginson DS, Yarusi B, Chan S, et al. Use of Human Papillomavirus 16 (HPV16) Cell Free DNA for Assessment of Response to Chemoradiation in HPV-Associated Oropharyngeal Cancer. Int. J. Radiat. Oncol. Biol. Phys. 2015;93(3S). https://doi.org/10.1016/j.ijrobp.2015.07.188

  30. 30.

    Ahn SM, Chan JY, Zhang Z, Wang H, Khan Z, Bishop JA, et al. Saliva and plasma quantitative polymerase chain reaction-based detection and surveillance of human papillomavirus-related head and neck cancer. JAMA Otolaryngol Head Neck Surg. 2014;140(9):846–54. https://doi.org/10.1001/jamaoto.2014.1338.

    Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Wang Y, Springer S, Mulvey CL, Silliman N, Schaefer J, Sausen M, et al. Detection of somatic mutations and HPV in the saliva and plasma of patients with head and neck squamous cell carcinomas. Sci Transl Med. 2015;7(293):293ra104. https://doi.org/10.1126/scitranslmed.aaa8507.

  32. 32.••

    Chera BS, Kumar S, Beaty BT, Marron D, Jefferys S, Green R, 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;25(15):4682–4690. https://doi.org/10.1158/1078-0432.CCR-19-0211. Epub 2019 May 14. Multi-institutional prospective biomarker trial defining clearance kinetics associated with disease control after CRT for HPV-positive OPSCC. Rapid clearance profile may predict likelihood of disease control.

  33. 33.

    Misawa K, Imai A, Matsui H, Kanai A, Misawa Y, Mochizuki D, et al. Identification of novel methylation markers in HPV-associated oropharyngeal cancer: genome-wide discovery, tissue verification and validation testing in ctDNA. Oncogene. 2020;39(24):4741–55. https://doi.org/10.1038/s41388-020-1327-z Epub 2020 May 15.

  34. 34.

    Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359(11):1116–27. https://doi.org/10.1056/NEJMoa0802656.

  35. 35.

    Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a southwest oncology group study. J Clin Oncol. 1992;10(8):1245–51. https://doi.org/10.1200/JCO.1992.10.8.1245.

  36. 36.

    Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G Jr, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019;394(10212):1915–28. https://doi.org/10.1016/S0140-6736(19)32591-7.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Jeannot E. V. Becette, M. Campitelli, M.a. Calméjane, E. Lappartient, E. ruff, et al. circulating human papillomavirus DNA detected using droplet digital PCR in the serum of patients diagnosed with early stage human papillomavirus-associated invasive carcinoma. J Pathol Clin Res. 2016;2(4):201–9. https://doi.org/10.1002/cjp2.47.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Tang KD, Baeten K, Kenny L, Frazer IH, Scheper G, Punyadeera C. Unlocking the potential of saliva-based test to detect HPV-16-driven Oropharyngeal Cancer. Cancers (Basel). 2019;11(4):473. https://doi.org/10.3390/cancers11040473.

    CAS  Article  Google Scholar 

  39. 39.

    Tang KD, Vasani S, Taheri T, Walsh LJ, Hughes BGM, Kenny L, et al. An occult HPV-driven Oropharyngeal squamous cell carcinoma discovered through a saliva test. Front Oncol. 2020;10:408. https://doi.org/10.3389/fonc.2020.00408.

  40. 40.

    Wang Y, Springer S, Mulvey CL, Silliman N, Schaefer J, Sausen M, et al. Detection of somatic mutations and HPV in the saliva and plasma of patients with head and neck squamous cell carcinomas. Sci Transl Med. 2015;7(293):293ra104. https://doi.org/10.1126/scitranslmed.aaa8507.

  41. 41.

    Rustin GJ, van der Burg ME, Griffin CL, Guthrie D, Lamont A, Jayson GC, et al. Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial. Lancet. 2010;376(9747):1155–63. https://doi.org/10.1016/S0140-6736(10)61268-8.

    Article  PubMed  Google Scholar 

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Correspondence to Paul L Swiecicki MD.

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Dermody, S.M., Haring, C.T., Bhambhani, C. et al. Surveillance and Monitoring Techniques for HPV-Related Head and Neck Squamous Cell Carcinoma: Circulating Tumor DNA. Curr. Treat. Options in Oncol. 22, 21 (2021). https://doi.org/10.1007/s11864-021-00821-8

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Keywords

  • ctDNA
  • HPV
  • Head and neck cancer
  • Biomarker
  • Oropharyngeal cancer