Sentinel lymph node biopsy was historically inconsistent in CSCC because a positive finding had no approved systemic treatment path. With adjuvant cemiplimab's approval, identifying microscopic nodal disease now directly impacts treatment eligibility, potentially making the procedure a new standard of care for certain high-risk patients.

Historically, discussing adjuvant therapy for Stage III colon cancer was quick and straightforward, while Stage II was complex. The advent of ctDNA testing has reversed this dynamic. Stage II decisions are now clearer (treat if positive), while Stage III discussions have become much longer and more nuanced as clinicians integrate ctDNA data with patient preferences.

With 72% response rates to neoadjuvant immunotherapy, surgeons are shifting from immediate, aggressive surgery to a "wait-and-see" approach. Shrinking the tumor first can turn a morbid, disfiguring operation into a much simpler procedure, fundamentally changing the initial surgical evaluation for cutaneous squamous cell carcinoma (CSCC).

The next frontier in CSCC isn't just about new drugs, but about optimizing existing ones. A key research area is determining the minimum number of immunotherapy doses required for an optimal response—potentially just one or two—to limit toxicity, reduce treatment burden, and personalize care for high-risk patients.

The InVigor11 study was the first to show that detecting recurrence via a ctDNA test before it's visible on scans is not just a prognostic sign, but an actionable clinical state. Intervening with therapy at this early stage was proven to improve patient outcomes, establishing a new paradigm for cancer surveillance.

In a subset analysis of the high-risk MONARCH-E trial, an inferred Oncotype score did not identify which patients benefited from the CDK4/6 inhibitor abemaciclib. This indicates that while such scores assess prognostic risk and guide chemotherapy decisions, they are not predictive biomarkers for selecting patients for this targeted therapy.

The RSClin tool integrates a patient's Oncotype DX score with their unique clinical-pathologic features, such as tumor size and grade. This provides a more accurate and personalized risk assessment, as the same genomic score can represent significantly different prognoses for patients who have low versus high clinical risk factors.

Instead of a rigid, pre-defined treatment plan, clinicians are adopting a "response-determined" approach for cutaneous squamous cell carcinoma. A tumor initially deemed unresectable can become operable after just one or two doses of immunotherapy, requiring dynamic, ongoing collaboration between surgical and medical oncology teams to adjust the plan.

The main barrier to widespread ctDNA use is not its proven ability to predict who will recur (prognostic value). The challenge is the emerging, but not yet definitive, data on its ability to predict a patient's response to a specific therapy (predictive value).