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 * Ab…