Measurable Residual Disease Detection Using Tumor-Informed ctDNA Surveillance After Curative-Intent Treatment in HPV-Independent Squamous Cell Carcinoma of the Head and Neck

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.