Plasma Circulating Tumor HPV DNA for the Surveillance of Cancer Recurrence in HPV-Associated Oropharyngeal Cancer

J Clin Oncol. 2020 Apr 1;38(10):1050-1058. doi: 10.1200/JCO.19.02444. Epub 2020 Feb 4.


Purpose: Plasma circulating tumor human papillomavirus DNA (ctHPVDNA) is a sensitive and specific biomarker of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). We investigated whether longitudinal monitoring of ctHPVDNA during post-treatment surveillance could accurately detect clinical disease recurrence.

Methods and materials: A prospective biomarker clinical trial was conducted among patients with nonmetastatic HPV-associated (p16-positive) OPSCC. All patients were treated with curative-intent chemoradiotherapy (CRT). Patients underwent a 3-month post-CRT positron emission tomography/computed tomography scan and were thereafter clinically evaluated every 2-4 months (years 1-2), then every 6 months (years 3-5). Chest imaging was performed every 6 months. Blood specimens were collected every 6-9 months for analysis of plasma ctHPVDNA using a multianalyte digital polymerase chain reaction assay. The primary endpoint was to estimate the negative predictive value (NPV) and positive predictive value (PPV) of ctHPVDNA surveillance.

Results: One hundred fifteen patients were enrolled, and 1,006 blood samples were analyzed. After a median follow-up time of 23 months (range, 6.1-54.7 months), 15 patients (13%) developed disease recurrence. Eighty-seven patients had undetectable ctHPVDNA at all post-treatment time points, and none developed recurrence (NPV, 100%; 95% CI, 96% to 100%). Twenty-eight patients developed a positive ctHPVDNA during post-treatment surveillance, 15 of whom were diagnosed with biopsy-proven recurrence. Sixteen patients had 2 consecutively positive ctHPVDNA blood tests, 15 of whom developed biopsy-proven recurrence. Two consecutively positive ctHPVDNA blood tests had a PPV of 94% (95% CI, 70% to 99%). Median lead time between ctHPVDNA positivity and biopsy-proven recurrence was 3.9 months (range, 0.37-12.9 months).

Conclusion: Detection of ctHPVDNA in two consecutive plasma samples during post-treatment surveillance has high PPV and NPV for identifying disease recurrence in patients with HPV-associated oropharyngeal cancer and may facilitate earlier initiation of salvage therapy.

Trial registration: NCT02281955 NCT03077243 NCT03161821.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alphapapillomavirus / genetics*
  • Biomarkers, Tumor / blood
  • Biomarkers, Tumor / genetics
  • Circulating Tumor DNA / blood*
  • Circulating Tumor DNA / genetics
  • Clinical Trials, Phase II as Topic
  • DNA, Viral / blood*
  • DNA, Viral / genetics
  • Female
  • Humans
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Neoplasm Recurrence, Local / blood*
  • Neoplasm Recurrence, Local / virology
  • Oropharyngeal Neoplasms / blood*
  • Oropharyngeal Neoplasms / therapy
  • Oropharyngeal Neoplasms / virology
  • Papillomavirus Infections / blood
  • Papillomavirus Infections / virology
  • Prospective Studies
  • Squamous Cell Carcinoma of Head and Neck / blood*
  • Squamous Cell Carcinoma of Head and Neck / therapy
  • Squamous Cell Carcinoma of Head and Neck / virology


  • Biomarkers, Tumor
  • Circulating Tumor DNA
  • DNA, Viral

Associated data