A Study on Using Cell-Free Tumor DNA (ctDNA) Testing to Decide When to StartRoutine Treatment in People With Human Papilloma Virus (HPV)- Associated Oropharynx Cancer (OPC)

Inclusion Criteria:

* Age ≥ 18
* ECOG 0-2
* HPV-16 squamous cell carcinoma of the oropharynx or HPV-16 head and neck squamous cell carcinoma of unknown primary . HPV status must be confirmed by in-situ hybridization.
* HPV ctDNA detectable by HPV digital PCR (Naveris assay) with a minimum of 50 copies/mL pre-operatively.
* Surgical resection of all gross disease with no gross disease visualized on post-operative imaging.

  o For patients with pT0 (unknown primary) evaluation for the primary should include PET/CT, direct laryngoscopy, ipsilateral tonsillectomy, and targeted biopsy. This should be followed by a neck dissection.
* Two, undetectable (\<1 copy/mL) post-operative HPV ctDNA within 2-6 weeks following surgery (blood drawn at least one week apart preferred).
* A minimum of one of the following pathologic criteria: (Arm A)

  * AJCC 7 Stage: pT0N1-N2b, pT1N1, pT2N1, or ≥pT3
  * AJCC 7 ≥pN2
  * Lymphovascular invasion
  * Perineural invasion
  * Close pathologic margin (≤ 3 mm)
* Signed informed consent form by the participant or their legally authorized representative (LAR).
* A minimum of one of the following pathologic criteria (Arm B):

  * Microscopic positive margin
  * Extracapsular extension
* Signed informed consent form by the participant or their legally authorized representative (LAR).

Additional criteria for Arm B only:

* Adequate hematologic function within 30 days prior to registration, defined as follows:

  * White Blood Count (WBC) ≥ 2 K/mcL
  * Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3
  * Platelets ≥ 100,000 cells/mm3
  * Hemoglobin ≥ 8.0 g/dl; Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable
* Adequate renal function within 30 days prior to registration, defined as follows:

  * Serum creatinine \< 1.5 mg/dl or creatinine clearance (CC) ≥ 50 ml/min determined by 24-hour collection or estimated by Cockcroft-Gault formula:
  * CCr male = \[(140 - age) x (wt in kg)\] divided by \[(Serum Cr mg/dl) x (72)\]
  * CCr female = 0.85 x (CrCl male)
* Adequate hepatic function within 30 days prior to registration, defined as follows:

  \- Bilirubin \< 2 mg/dl o AST or ALT \< 3 x the upper limit of normal
* Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential

Exclusion Criteria:

* Metastatic disease
* Non-HPV16 genotype (i.e. HPV-18,-31, -33, -35)
* Patients who receive surgery at outside institution. Exceptions can be made for high-volume surgical centers at the discretion of the PI/co-PI
* Prior head and neck radiation
* Patients without pre-operative HPV ctDNA or pre-operative HPV ctDNA ≤ 50 copies/mL
* Subjects with simultaneous primary cancers outside of the oropharynx

  o Note: Exceptions can be made for patients with simultaneous primaries outside of the oropharynx if determined by the PI/Co-PI, then the patient can proceed with protocol activities
* Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for 3 years or if cure rate from treatment at 5 years is 90% or greater

  o Note: Exceptions can be made for patients with prior invasive malignancy if determined by the PI/Co-PI, then the patient can proceed with protocol activities
* Prior systemic chemotherapy for the study cancer

  o Note: prior chemotherapy for a different cancer is allowable
* Severe, active co-morbidity defined as follows:

  * Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
  * Transmural myocardial infarction within the last 6 months
  * Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
  * Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization within 30 days of registration
  * Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
* Lack of ability to understand and willingness to sign a written informed consent and complete questionnaires.