ctHPV-DNA-basierte Präzisionsonkologie für Patienten mit Oropharynxkarzinom – wo stehen wir?

Zusammenfassung

Das humane Papillomavirus (HPV) ist im Kopf-Hals-Bereich ein gesicherter ätiologischer Faktor für die Entstehung von oropharyngealen Plattenepithelkarzinomen (engl. OPSCC). Die gute Überlebensrate rechtfertigt die derzeitige Diskussion einer Therapiedeeskalation für Patienten mit einem geringeren Risikoprofil. Ungeachtet des immunhistochemisch nachweisbaren Biomarkers p16INK4a besteht ein hoher Bedarf an diagnostischen und prognostischen Biomarkern, um eine valide Risikostratifizierung und Überwachung der Patienten unter Therapie und in der Nachsorge ermöglichen zu können. Die Liquid Biopsy, insbesondere in Form von Plasmaproben, hat aus diesem Grund in den letzten Jahren an Bedeutung gewonnen und wird bereits bei Epstein-Barr-Virus-assoziierten Nasopharynxkarzinomen zum Monitoring der Virus-DNA eingesetzt. Die zirkulierende Tumor-DNA (ctDNA), welche von dem Tumor in die Blutbahn abgegeben wird, lässt sich besonders bei Virus-assoziierten Karzinomen mit hoher Spezifität nachweisen. Die Detektion der viralen Onkogene E6 und E7 bei HPV-positiven OPSCC erfolgt überwiegend mittels droplet-digital/quantitativer PCR sowie Next Generation Sequencing. Die im Blutstrom erfassbare HPV-assoziierte DNA ist bei Diagnosestellung mit dem Tumorstadium und mit dem Auftreten von lokoregionalen sowie entfernten Metastasen assoziiert. Longitudinale Untersuchungen haben weiterhin ergeben, dass nachweisbare bzw. ansteigende ctHPV-DNA-Werte im Blut im Zusammenhang mit einem Scheitern der Therapie bzw. einem Rückfall der Erkrankung stehen. Eine Standardisierung des Verfahrens ist jedoch notwendig, bevor die Liquid Biopsy endgültig Einzug in die klinische Diagnostik erhält und eine valide Reflexion das Krankheitsgeschehen ermöglichen kann.

Abstract

Human papillomavirus (HPV) is an established etiologic factor for cancers in the head and neck region, specifically for Oropharyngeal Squamous Cell Carcinoma (OPSCC). The comparatively good overall survival justifies the current discussion regarding therapy de-escalation for patients with a low-risk profile. In addition to the immunohistochemistry-based biomarker p16INK4a, there is still a need for diagnostic and prognostic biomarkers that allow risk stratification and monitoring during therapy and follow-up of these patients. In recent years, liquid biopsy, especially in the form of plasma samples, has gained importance and is already used to monitor viral DNA in patients with Epstein-Barr virus-associated nasopharyngeal carcinoma. Circulating DNA (ctDNA) released by the tumor into the bloodstream is particularly suitable for a high specificity in detecting virus-associated tumors. Detection of viral E6 and E7 oncogenes in HPV-positive OPSCC is predominantly performed by droplet digital/quantitative PCR as well as next generation sequencing. Detection of circulating HPV-DNA derived from tumor cells (ctHPV-DNA) at diagnosis is associated with advanced tumor stage, locoregional and distant metastases. Longitudinal studies have further demonstrated that detectable and/or increasing ctHPV-DNA levels are associated with treatment failure and disease relapse. However, a standardization of the diagnostic procedure is necessary before introducing liquid biopsy into the clinical routine. In the future, this might allow a valid reflection of disease progression in HPV-positive OPSCC.

Schlüsselwörter

Oropharynxkarzinom - humane Papillomaviren - Kopf-Hals-Karzinom - Liquid Biopsy - ctHPV-DNA - Biomarker - Prognose

Keywords

human papillomavirus - head and neck squamous cell carcinoma - liquid biopsy - ctHPV-DNA - biomarker - oropharyngeal squamous cell carcinoma

Publication History

Received: 14 February 2023

Accepted after revision: 08 May 2023

Article published online:
26 June 2023

• Literatur

• 1 Mandel P, Metais P. Nuclear Acids In Human Blood Plasma. C R Seances Soc Biol Fil 1948; 142: 241-243
• 2 Thierry AR, El Messaoudi S, Gahan PB. et al. Origins, structures, and functions of circulating DNA in oncology. Cancer Metastasis Rev 2016; 35: 347-376
• 3 Khier S, Lohan L. Kinetics of circulating cell-free DNA for biomedical applications: critical appraisal of the literature. Future Sci OA 2018; 4: FSO295
• 4 Chan KCA, Woo JKS, King A. et al. Analysis of Plasma Epstein-Barr Virus DNA to Screen for Nasopharyngeal Cancer. N Engl J Med 2017; 377: 513-522
• 5 Li W, Chen J, Liang B. et al. Long-term monitoring of dynamic changes in plasma EBV DNA for improved prognosis prediction of nasopharyngeal carcinoma. Cancer Med 2021; 10: 883-894
• 6 Ho HL, Jiang Y, Chiang CL. et al. Efficacy of liquid biopsy for disease monitoring and early prediction of tumor progression in EGFR mutation-positive non-small cell lung cancer. PLoS One 2022; 17: e0267362
• 7 Faraji F, Rettig EM, Tsai HL. et al. The prevalence of human papillomavirus in oropharyngeal cancer is increasing regardless of sex or race, and the influence of sex and race on survival is modified by human papillomavirus tumor status. Cancer 2019; 125: 761-769
• 8 Wittekindt C, Wagner S, Bushnak A. et al. Increasing Incidence rates of Oropharyngeal Squamous Cell Carcinoma in Germany and Significance of Disease Burden Attributed to Human Papillomavirus. Cancer Prev Res (Phila) 2019; 12: 375-382
• 9 Lechner M, Jones OS, Breeze CE. et al. Gender-neutral HPV vaccination in the UK, rising male oropharyngeal cancer rates, and lack of HPV awareness. Lancet Infect Dis 2019; 19: 131-132
• 10 Mehanna H, Taberna M, Buchenwald Cv. et al. Prognostic implications of p16 and HPV discordance in oropharyngeal cancer (HNCIG-EPIC-OPC): a multicentre, multinational, individual patient data analysis. Lancet Oncol 2023;
• 11 Faraji F, Eisele DW, Fakhry C. Emerging insights into recurrent and metastatic human papillomavirus-related oropharyngeal squamous cell carcinoma. Laryngoscope Investig Otolaryngol 2017; 2: 10-18
• 12 Ang KK, Harris J, Wheeler R. et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010; 363: 24-35
• 13 Mattox AK, D’Souza G, Khan Z. et al. Comparison of next generation sequencing, droplet digital PCR, and quantitative real-time PCR for the earlier detection and quantification of HPV in HPV-positive oropharyngeal cancer. Oral Oncol 2022; 128: 105805
• 14 Leung E, Han K, Zou J. et al. HPV Sequencing Facilitates Ultrasensitive Detection of HPV Circulating Tumor DNA. Clin Cancer Res 2021; 27: 5857-5868
• 15 Joosse SA, Pantel K. Detection of Hypomethylation in Long-ctDNA. Clin Chem 2022; 68: 1115-1117
• 16 Ekanayake Weeramange C, Liu Z, Hartel G. et al. Salivary High-Risk Human Papillomavirus (HPV) DNA as a Biomarker for HPV-Driven Head and Neck Cancers. J Mol Diagn 2021; 23: 1334-1342
• 17 Pascual J, Attard G, Bidard FC. et al. ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group. Ann Oncol 2022; 33: 750-768
• 18 Cao H, Banh A, Kwok S. et al. Quantitation of human papillomavirus DNA in plasma of oropharyngeal carcinoma patients. Int J Radiat Oncol Biol Phys 2012; 82: e351-358
• 19 Ahn SM, Chan JY, Zhang Z. 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: 846-854
• 20 Damerla RR, Lee NY, You D. et al. Detection of Early Human Papillomavirus-Associated Cancers by Liquid Biopsy. JCO Precis Oncol 2019; 3
• 21 Jeannot E, Becette V, Campitelli M. 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: 201-209
• 22 Lee JY, Garcia-Murillas I, Cutts RJ. 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: 876-883
• 23 Nguyen B, Meehan K, Pereira MR. et al. A comparative study of extracellular vesicle-associated and cell-free DNA and RNA for HPV detection in oropharyngeal squamous cell carcinoma. Sci Rep 2020; 10: 6083
• 24 Reder H, Taferner VF, Wittekindt C. et al. Plasma Cell-Free Human Papillomavirus Oncogene E6 and E7 DNA Predicts Outcome in Oropharyngeal Squamous Cell Carcinoma. J Mol Diagn 2020; 22: 1333-1343
• 25 Wuerdemann N, Jain R, Adams A. et al. Cell-Free HPV-DNA as a Biomarker for Oropharyngeal Squamous Cell Carcinoma-A Step Towards Personalized Medicine?. Cancers (Basel) 2020; 12
• 26 Siravegna G, O’Boyle CJ, Varmeh S. et al. Cell-Free HPV DNA Provides an Accurate and Rapid Diagnosis of HPV-Associated Head and Neck Cancer. Clin Cancer Res 2022; 28: 719-727
• 27 Rettig EM, Faden DL, Sandhu S. et al. Detection of circulating tumor human papillomavirus DNA before diagnosis of HPV-positive head and neck cancer. Int J Cancer 2022; 151: 1081-1085
• 28 Busch CJ, Hoffmann AS, Viarisio D. et al. Detection of stage I HPV-driven oropharyngeal cancer in asymptomatic individuals in the Hamburg City Health Study using HPV16 E6 serology – A proof-of-concept study. EClinicalMedicine 2022; 53: 101659
• 29 Rutkowski TW, Mazurek AM, Snietura M. 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: 167
• 30 O’Boyle CJ, Siravegna G, Varmeh S. et al. Cell-free human papillomavirus DNA kinetics after surgery for human papillomavirus-associated oropharyngeal cancer. Cancer 2022; 128: 2193-2204
• 31 Veyer D, Wack M, Mandavit M. et al. HPV circulating tumoral DNA quantification by droplet-based digital PCR: A promising predictive and prognostic biomarker for HPV-associated oropharyngeal cancers. Int J Cancer 2020; 147: 1222-1227
• 32 Dahlstrom KR, Li G, Hussey CS. et al. Circulating human papillomavirus DNA as a marker for disease extent and recurrence among patients with oropharyngeal cancer. Cancer 2015; 121: 3455-3464
• 33 Rettig EM, Wang AA, Tran NA. 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; 148: 1120-1130
• 34 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; 25: 4682-4690
• 35 Cao Y, Haring CT, Brummel C. et al. Early HPV ctDNA Kinetics and Imaging Biomarkers Predict Therapeutic Response in p16+ Oropharyngeal Squamous Cell Carcinoma. Clin Cancer Res 2022; 28: 350-359
• 36 Tanaka H, Takemoto N, Horie 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 2021; 148: 995-1005
• 37 Warlow SJ, Adamowicz M, Thomson JP. et al. Longitudinal measurement of HPV copy number in cell-free DNA is associated with patient outcomes in HPV-positive oropharyngeal cancer. Eur J Surg Oncol 2022; 48: 1224-1234
• 38 Berger BM, Hanna GJ, Posner MR. 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; 28: 4292-4301
• 39 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; 38: 1050-1058
• 40 Haring CT, Bhambhani C, Brummel C. et al. Human papilloma virus circulating tumor DNA assay predicts treatment response in recurrent/metastatic head and neck squamous cell carcinoma. Oncotarget 2021; 12: 1214-1229
• 41 Hanna GJ, Supplee JG, Kuang Y. et al. Plasma HPV cell-free DNA monitoring in advanced HPV-associated oropharyngeal cancer. Ann Oncol 2018; 29: 1980-1986
• 42 Routman DM, Kumar S, Chera BS. et al. 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; 113: 530-538
• 43 Ward MC, Miller JA, Walker GV. et al. The economic impact of circulating tumor-tissue modified HPV DNA for the post-treatment surveillance of HPV-driven oropharyngeal cancer: A simulation. Oral Oncology 2022;
• 44 Adilbay D, Lele S, Pang J. et al. Circulating Human Papillomavirus DNA in Head and Neck Squamous Cell Carcinoma: Possible Applications and Future Directions. Cancers (Basel) 2022; 14 (23) 5946