This study will test the ability of a personalized blood test to determine which head and neck cancer patients will have a recurrence after treatment.

This is a two-arm, prospective, observational study of patients with human papillomavirus (HPV)-independent head and neck squamous cell carcinoma (HNSCC) who are receiving curative-intent treatment. Arm 1 will consist of patients who undergo surgery. Arm 2 will consist of patients who undergo chemoradiotherapy.

The study will test the following hypotheses:

1. That applying a tumor-informed minimal residual disease (MRD) assay after completion of curative-intent treatment will accurately discriminate between patients who will eventually experience recurrence (those are MRD positive) and patients who will remain disease-free (those who are MRD negative). The hypothesis is that patients who have detectable ctDNA following treatment-MRD positive patients-will experience recurrent disease within 2 years, while patients who have no detectable ctDNA-MRD negative patients-will remain disease free at 2 years.
2. That measuring MRD after completion of curative-intent treatment will provide a lead time from detectable to clinical diagnosis of recurrent disease of at least 3 months.

The primary outcome is 2-year DFS in patients with detectable vs no detectable ctDNA two weeks after treatment completion.

The study will accrue 75 patients, who will be followed for a minimum of 2 years.

Subjects will have blood draws before, during and following treatment at regular intervals for testing with the assay (Haystack MRD™)

Inclusion Criteria:

• Newly diagnosed AJCC 8th edition Stage III-IVB mucosal SCC of the head and neck, which includes tumors arising from the oral cavity, nasal cavity, paranasal sinuses, nasopharynx, oropharynx, hypopharynx, and larynx.
• Available tissue for tumor-informed ctDNA panel creation.
• Definitive treatment with standard of care surgery or chemoradiotherapy is planned to be administered at Massachusetts Eye and Ear Institute (MEEI) or within the Massachusetts General Hospital (MGH) Cancer Center (including but not limited to the Boston, Danvers, and Newton-Wellesley locations).

Exclusion Criteria:

• Patients <18 years of age
• Patients receiving non-standard of care therapy as determined by the clinical investigator
• Participants who have undergone prior surgical resection, excisional biopsy, radiation, and/or chemotherapy for the treatment of HNSCC. Prior incisional biopsies are permitted. Discrepant cases will be reviewed by study PI.
• Participants who are receiving any investigational agents at the time of enrollment.
• Participants with AJCC Stage IVC HNSCC, which includes patients with biopsy-confirmed distant metastatic HNSCC, including but not limited to metastatic spread to the lungs, bones, or liver.
• Active non-HNSCC malignancy.
• Active pregnancy during treatment.

Patients with Stage III-IVB mucosal squamous cell carcinoma of the head and neck