Molecular and Clinicopathological Biomarkers in the Neoadjuvant Treatment of Patients with Advanced Resectable Melanoma

Abstract

Neoadjuvant systemic therapy is emerging as the best medical practice in patients with resectable stage III melanoma. As different regimens are expected to become available in this approach, the improved optimization of treatment strategies is required. Personalization of care in each individual patient-by precisely determining the disease-related risk and the most efficient therapeutic approach-is expected to minimize disease recurrence, but also the incidence of treatment-related adverse events and the extent of surgical intervention. This can be achieved through validation and clinical application of predictive and prognostic biomarkers. For immune checkpoint inhibitors, there are no validated predictive biomarkers until now. Promising predictive molecular biomarkers for neoadjuvant immunotherapy are tumor mutational burden and the interferon-gamma pathway expression signature. Pathological response to neoadjuvant treatment is a biomarker of a favorable prognosis and surrogate endpoint for recurrence-free survival in clinical trials. Despite the reliability of these biomarkers, risk stratification and response prediction in the neoadjuvant setting are still unsatisfactory and represent a critical knowledge gap, limiting the development of optimized personalized strategies in everyday practice.

Keywords: neoadjuvant immunotherapy; neoadjuvant-targeted therapy; predictive factors; prognostic factors.

Figure 1

Pathological response to immunotherapy; (A) lymph node with both abundant fields of melanophages (40×) with fibrosis (*) and lymphohistiocytic infiltration (#), (B) fibrosis in higher magnification (100×) and (C) lymphohistiocytic infiltration in higher magnification (100×); (D) the typical response “mixture” of different reactions (20×), (E) sometimes the melanophages present very dense melanin (400×), which could be diagnostically challenging; (F) necrosis can be massive or only focal–marked with dashed line (400×).

Figure 2

A role of interferon-gamma signaling in the development of anti-tumor response during anti-PD-1 plus anti-CLTA-4 immunotherapy. The impact of chemokines CXCL9, CXCL10 and CXCL11 on antigen-presenting cells (APC) depicted. Tumor-associated antigen (TAA) presentation on MHC II (HLA-DR) molecule to CD4⁺ T-cells. Molecules marked with (*) include translation products of mRNAs, which are measured to determine a 10-gene interferon-gamma (IFN-γ) signature score, including Perforin 1 and Granzyme A involved in cytotoxic melanoma cell killing by CD8⁺ T cells.