The purpose of this study is to test the potential for a liquid biopsy assay to detect residual disease after surgery in patients with cutaneous squamous cell carcinoma as well as the potential for this assay to monitor response to immunotherapy treatment.

The study aims to better understand whether circulating tumor DNA, or ctDNA, a type of personalized blood test informed by the tumor, can help monitor recurrence and treatment responses in patients with cutaneous squamous cell carcinoma (CSCC), especially during and after treatment. Blood samples will be collected during regular treatment visits or through mobile phlebotomy visits, and analyzed to study how ctDNA levels change over time. Participants will be in the study for 2 years.

Circulating tumor DNA consists of small fragments of DNA shed into the bloodstream by cancer cells. It may serve as a non-invasive biomarker for detecting and monitoring CSCC, offering insights into tumor treatment response and/or progression. ctDNA can provide a "liquid biopsy," allowing real-time tracking of tumor dynamics. Specifically, the study is researching how ctDNA levels change in patients undergoing surgery, immunotherapy, or other standard treatments. The goal is to see if ctDNA can serve as a biomarker to better understand treatment response and detect potential progression/ recurrence of the cancer.

This study does not involve any experimental drugs or devices. All drugs and treatments administered to participants, including surgery and immunotherapy, are part of standard of care. The ctDNA blood test is being used as a research tool and is not currently approved by the U.S. Food and Drug Administration (FDA) for monitoring CSCC. The study aims to evaluate its potential future use as a reliable biomarker.

Post-Operative Cohort

Inclusion Criteria:

• Patients with surgically resectable primary CSCC with PNI (>0.1mm caliber nerve) or at least 2 high-risk features defined as size > 2cm, recurrent CSCC, LVI, immunosuppressed, poorly differentiated, and/or invasion >6mm/beyond subcutaneous fat;
• Patients with surgically resectable regional metastases not receiving neoadjuvant therapy

Exclusion Criteria:

• Patients with Cutaneous Squamous Cell Carcinoma not amenable to surgical resection
• Patients receiving or undergoing systemic therapies.

Neoadjuvant Cohort

Inclusion Criteria:

• Patients with resectable AJCC (8th ed) Stage II, III or IV(M0) CSCC treated with neoadjuvant immunotherapy as part of standard care.

Exclusion Criteria:

• Patients ineligible for neoadjuvant treatment.

Definitive Immunotherapy Cohort

Inclusion Criteria:

• Patients with unresectable locally advanced or metastatic CSCC, AJCC (8th ed) Stage II, III, or IV), receiving immunotherapy as part of standard of care.

Exclusion Criteria:

• Patients undergoing systemic therapies outside the standard of care or enrolled in conflicting clinical trials.

Patients ages 18 and older, who have been diagnosed with cutaneous squamous cell carcinoma (CSCC)