Despite both being keratinocyte-derived skin cancers, basal cell carcinoma (BCC) responds much less robustly to immunotherapy than cutaneous squamous cell carcinoma (CSCC). The pathologic complete response rate to perioperative PD-1 inhibition in BCC is only 23%, less than half the 51% seen in CSCC, highlighting their distinct immunobiology.

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).

In a pivotal neoadjuvant trial of cemiplimab for CSCC, none of the 40 patients who achieved a pathologic complete response (path CR) had relapsed at long-term follow-up. This suggests that path CR can be used as a powerful early indicator of long-term disease control and potential cure.

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.

While nomograms are useful for quantifying risk in primary CSCC tumors, their predictive power diminishes significantly once a patient has a regional recurrence. Clinicians should use them cautiously in the recurrent setting, as their original design and validation are based on primary tumors.

Experts argue that radiation therapy is often wrongly perceived as a salvage or adjuvant option. For many patients with early-stage basal or squamous cell carcinomas, it offers local control rates over 95%, comparable to surgery, and should be presented as a primary alternative, especially when cosmetic outcomes are a priority.

In the adjuvant (post-surgery) setting, Disease-Free Survival (DFS) is a more crucial and patient-relevant endpoint than Progression-Free Survival (PFS) is in the metastatic setting. A DFS event signifies the cancer's return, a major psychological and clinical blow, distinct from the growth of an already-known tumor in the metastatic context.

Experts advise against using gene expression profiling to escalate care for CSCC (e.g., deciding to add systemic therapy). Its primary utility is in de-escalation: a low-risk profile can provide an additional data point to support a decision for observation in a borderline high-risk case, helping to avoid overtreatment.

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.