Different Response to Immunotherapy According to Melanoma Histologic Subtype

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Superficial spreading melanoma (SSM) and nodular melanoma (NM) are the most common melanoma subtypes with distinct biological characteristics.
• Understanding subtype-specific responses to cancer immunotherapy is crucial for optimizing treatment strategies.

Purpose of the Study:

• To investigate the association between melanoma histologic subtype (NM vs. SSM) and patient outcomes following treatment with immune checkpoint inhibitors (anti-PD-1 and/or anti-CTLA-4).
• To identify molecular differences, including gene expression and pathway enrichment, between NM and SSM in advanced melanoma patients.

Main Methods:

• Retrospective analysis of advanced melanoma patients treated with anti-PD-1 and/or anti-CTLA-4, categorizing outcomes by primary tumor subtype (NM vs. SSM).
• Whole-exome and whole-transcriptome sequencing were performed on a subset of NM and SSM tumors to compare genetic and transcriptomic profiles.
• Statistical analyses included response rates, progression-free survival, overall survival, and multivariable analysis adjusting for prognostic factors.

Main Results:

• Nodular melanoma (NM) patients exhibited significantly higher overall response rates (52.4% vs. 20.5%, P=0.02) compared to superficial spreading melanoma (SSM) patients.
• Median progression-free survival (13.9 vs. 3.2 months, P=0.032) and overall survival (44.5 vs. 12 months, P=0.002) were substantially longer for NM patients.
• Transcriptomic analysis revealed overexpression of 266 genes in NM, enriched in immune-related pathways such as antigen presentation and interferon gamma response, with no significant differences in tumor mutational burden.

Conclusions:

• Melanoma histologic subtype is a significant factor influencing patient response and survival outcomes in immunotherapy.
• Nodular melanoma appears to be more responsive to immune checkpoint inhibitor therapy than superficial spreading melanoma.
• Distinct molecular pathways, particularly those related to immune response, characterize NM and may contribute to its differential response to immunotherapy.