Journal Article

Genomic and tumour microenvironmental biomarkers of immune checkpoint inhibitor response in advanced Taiwanese melanoma

Wang, Yu‐Chao, Tan, Kien Thiam, Wang, Yeh‐Han, Chen, Shu‐Jen, Chen, Chiao‐Ping, Huang, Wen‐Kuan, Wu, Chiao‐En, Huang, Yen‐Lin, Chang, John Wen‐Cheng, Wu, Chia‐Ling, Hsieh, Jia‐Juan, Huang, Chien‐Jung, Chang, Yao‐Yu

2023

Overview

Objective Genomic biomarkers predicting immune checkpoint inhibitor (ICI) treatment outcomes for Asian metastatic melanoma have been rarely reported. This study presents data on next‐generation sequencing (NGS) and tumour microenvironment biomarkers in 33 cases. Methods Thirty‐three patients with advanced melanoma, who underwent ICI treatment at the Chang Gung Memorial Hospital in Taiwan, were recruited. The study evaluated clinical outcomes, including response rate, disease control rate, progression‐free survival (PFS) rate and overall survival (OS) rate. Archived tissue samples from 33 cases were subjected to NGS by ACTOnco, and ACTTME was employed in 25 cases. Results The most prevalent driver mutations were BRAF mutations (24.2%), followed by NRAS (15.2%), KIT (12.1%), KRAS (9.1%) and NF1 (9.1%) mutations. Acral/mucosal melanomas exhibited distinct mutation patterns compared to non‐acral melanomas. Tumour mutational burden estimated using ACTOnco was not associated with ICI efficacy. Notably, genetic alterations in the p53 pathway (CDKNA2 loss, MDM2 gain/amplification and TP53 mutation) accounted for 36.4% and were significantly associated with unfavourable PFS (median PFS 2.7 months vs. 3.9 months, P = 0.0394). Moreover, 26 genes were identified as differentially expressed genes that were upregulated in patients with clinical benefits compared to those without benefits. Four genes, GZMH, GZMK, AIM2 and CTLA4, were found to be associated with both PFS and OS. Conclusion Genetic alterations in the p53 pathway may be critical in Asian patients with melanoma undergoing ICI treatment. Further investigation is required to explore this mechanism and validate these findings. The genetic landscape of melanoma response to immune checkpoint inhibitors (ICIs) has been previously investigated, but without correlation with modulation of the tumour microenvironment in clinical survival and treatment outcomes. We used next‐generation sequencing to define the genetic biomarkers of Asian melanoma associated with ICI response. The p53 pathway (CDKN2A/MDM2/TP53) is a prognostic factor for progression‐free survival after ICI treatment in Taiwanese patients with melanoma.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Biomarkers / Clinical outcomes / CTLA-4 protein / Disease control / Genomes / genomic and TME biomarkers / Genomics / ICIs / Immune checkpoint inhibitors / Immune response / Immunotherapy / MDM2 protein / Medical prognosis / Melanoma / Metastases / Mutation / Next-generation sequencing / Original / p53 / p53 Protein / Patients / Skin cancer / Survival / Tumor microenvironment / Tumors