Association of Oral Human Papillomavirus DNA Persistence With Cancer Progression After Primary Treatment for Oral Cavity and Oropharyngeal Squamous Cell Carcinoma

Carole Fakhry, Amanda L Blackford, Geoff Neuner, Weihong Xiao, Bo Jiang, Amit Agrawal, Maura L Gillison

From JAMA Oncology, July 2019; 5(7):985-992.

Article Review by Theresa Guo, MD

Background / Hypothesis
Recent retrospective studies have shown that detection of HPV-16 DNA in oral rinse of HPV+ oropharyngeal cancer patients may predict increased risk for
recurrence. Therefore, a prospective study was designed to evaluate whether detection of HPV
DNA in oral rinses was able to predict clinical disease course.

Design
Multi-institutional prospective study enrolling patients diagnosed with oropharyngeal or oral cavity cancer. Oral rinses were collected at the time of diagnosis, after primary therapy, weekly during radiotherapy and at the completion of therapy. Rinses were tested for DNA of 37 HPV types by PCR.

Summary of Results
396 patients were enrolled including 217 oropharyngeal and 170 oral cavity patients, with 202 HPV-positive and 194 HPV-negative patients. At the time of diagnosis, oral HPV-16 DNA was 81% sensitive and 100% sensitive for HPV-16 positive tumors, and higher T stage was associated with oral HPV detection. In HPV-negative patients, oral HPV DNA was detected in 12.4% of patients. During treatment, tumor specific HPV type or “tumor-type HPV” decreased significantly during treatment, but non tumor-type HPV did not change. Tumor-type HPV was present in 14.3% of HPV-positive patients after completion of primary therapy, and recurrence rates were significantly higher than those without detectable DNA (45.3% vs. 12.2%). Persistent tumor-type DNA in oral rinses was significantly associated with increased risk of death (adjusted HR 6.61, p=0.003) as well as local (adjusted HR 9.81, p<0.001) and regional (adjusted HR 5.75, p=0.002) recurrence, but not distant recurrence.

Strengths

• Large prospectively collected cohort including nearly 400 patients with half of the
  cohort being HPV-positive and half being HPV-negative, including both oral cavity and
  oropharynx primary tumors (which are most likely to shed DNA into saliva).
• Rigorous testing of 37 HPV subtypes within tumor as well as saliva samples.
• Robust data on dynamics of tumor-type HPV DNA throughout treatment including
  before and after surgery, as well as weekly during radiation treatment.

 Weaknesses

• Lack data on plasma sampling to supplement oral rinses. The authors found that while
  oral rinse HPV DNA could predict locoregional recurrence, it was not associated with
  distant recurrence. Predicting distant recurrence may require plasma sampling for
  detection.
• Follow up time was limited to a median of 2.6 years. While most recurrences in
  oropharyngeal cancer occur within 2 years, some data has shown late recurrences from HPV-positive tumors. The authors hypothesize that persistent HPV DNA likely represents subclinical disease that results in recurrence, thus it is unknown whether persistent HPV infection would be able to predict late recurrences.

Key Points

• Oral HPV is detectable in 80% of patients with HPV-positive oropharyngeal cancer at the time of diagnosis.
• Unlike EBV viral load in nasopharyngeal cancer, viral load or presence of HPV DNA at the time of diagnosis was not associated with clinical outcomes.
• Detection of HPV is complicated by prevalence of non-tumor related HPV infections. This study highlights some of the nuances of using oral HPV as a surveillance biomarker, as only tumor-type HPV reflected the clinical disease course. There were no changes during treatment for viral load of non-tumor-type HPV. Furthermore, HPV-negative patients also demonstrated 12.4% prevalence of HPV DNA, and risk of infection in these patients was associated with the same risk factors for HPV infection in the general population, including male sex and number of lifetime sexual partners.
• Active smoking was associated with persistent tumor-type DNA.
• Persistent tumor-type HPV DNA is associated with both worse survival and locoregional recurrence. Future trial designs may consider additional therapy such as immunotherapy for patients with persistent HPV DNA after treatment completion.

From the Basic Science/Translational Service
Jeffrey C. Liu MD Vice Chair
Richard Wong MD Chair

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Theresa Guo

I am from Cleveland, Ohio where I received my medical degree from the Cleveland Clinic Lerner College of Medicine. I completed my Otolaryngology residency training at Johns Hopkins Hospital, and will be pursuing advanced fellowship training in Head & Neck Cancer at MD Anderson in Houston, Texas. My clinical and research interests are in advancing the treatment of head and neck cancer. In particular, I am interested in genetic profiling of head and neck tumors with poor prognosis and predicting treatment response.

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