New Diagnostic and Therapeutic Paradigms in Melanoma Management

At EADO 2025, Prof Dr Alexander Eggermont from the UMC Utrecht, The Netherlands, gave a nice presentation on new diagnostic and therapeutic paradigms in melanoma management. Recent developments in diagnostic testing and neoadjuvant immunotherapy are fundamentally changing the management of melanoma. These advances are expected to lead to a significant reduction in surgical interventions, reshaping the traditional treatment pathways.

One of the key innovations is the integration of a gene expression profile (GEP) with two known clinical-pathologic factors—patient age and Breslow thickness—into a single algorithm known as CP-GEP. This test, based on a panel of eight genes with independent prognostic value, can be performed using standard pathology techniques and requires only a few sections from the primary tumour. The CP-GEP provides a robust biological risk assessment for relapse, distinguishing between low-risk and high-risk profiles, even in early-stage melanoma. This is especially relevant for the large population of stage I and IIA melanoma patients, who typically have thin tumours and are considered low risk. Despite this, they account for a substantial portion of melanoma-related deaths. Sentinel lymph node biopsies are rarely performed in this group due to their low yield, yet CP-GEP testing offers a non-invasive, highly sensitive method to identify high-risk biology. Data from large patient cohorts demonstrate that this test effectively predicts which early-stage patients will relapse, without requiring surgical lymph node staging. Low-risk individuals can be followed with minimal intervention, while high-risk patients can receive closer surveillance.

The second major change is the shift in management of patients with pathologically involved lymph nodes. The emerging standard is to begin with neoadjuvant immunotherapy rather than immediate surgery. Trials using anti-PD-1 monotherapy or combinations with CTLA-4 inhibitors have shown high rates of pCR, often exceeding 50–70%. This approach leverages the immune-priming environment of the lymph nodes, allowing for expansion and diversification of tumour-specific T cell clones. Patients achieving major or complete responses can often avoid lymph node dissection altogether, with durable remission rates. 

Together, these two paradigm shifts—CP-GEP-based biological risk stratification and neoadjuvant immunotherapy—may reduce the need for sentinel lymph node biopsies and therapeutic lymph node dissections by over 50%, and in some cases up to 80%. This results in fewer surgeries, less morbidity, and more personalized treatment.

Looking ahead, the future of melanoma care will be centered around biology-driven decision making. A standardised molecular test on the primary tumour will stratify patients according to relapse risk. Those with a low-risk profile will be reassured and placed on minimal follow-up schedules, while high-risk patients—often unexpectedly found among early-stage melanomas—will be closely monitored. If relapse occurs, the first-line salvage strategy will not be surgery, but neoadjuvant immunotherapy, offering up to 70% cure rates.

This shift is equally relevant to other tumour types. Cutaneous squamous cell carcinoma follows a similar immunologic pattern. While large tumours may still require limited surgical cleanup after immunotherapy, smaller tumours, especially those in cosmetically sensitive facial areas, can often achieve complete responses with anti-PD-1 monotherapy alone. This avoids the need for disfiguring surgery, with response rates already exceeding 70–80% in early studies.

The paradigm is also expanding into other malignancies. MSI-high rectal cancers demonstrate near-universal complete response rates to neoadjuvant PD-1 blockade, removing the need for rectal excision. Similarly, in up to half of muscle-invasive bladder cancers, immunotherapy is enabling bladder preservation without cystectomy. These trends reflect a broader transformation in oncology, with immune-based neoadjuvant treatment reducing or eliminating major surgeries across multiple tumour types.