Tumor immunogenomic signatures improve a prognostic model of melanoma survival

Abstract

Background Tumor mutation burden (TMB) has been associated with melanoma immunotherapy (IT) outcomes, including survival. We explored whether combining TMB with immunogenomic signatures recently identified by The Cancer Genome Atlas (TCGA) can refine melanoma prognostic models of overall survival (OS) in patients not treated by IT. Methods Cox proportional-hazards (Cox PH) analysis was performed on 278 metastatic melanomas from TCGA not treated by IT. In a discovery and two validation cohorts Cox PH models assessed the interaction between TMB and 53 melanoma immunogenomic features to refine prediction of melanoma OS. Results Interferon-γ response (IFNγRes) and macrophage regulation gene signatures (MacReg) combined with TMB significantly associated with OS (p = 8.80E−14). We observed that patients with high TMB, high IFNγRes and high MacReg had significantly better OS compared to high TMB, low IFNγRes and low MacReg (HR = 2.8, p = 3.55E−08). This association was not observed in low TMB patients. Conclusions We report a model combining TMB and tumor immune features that significantly improves prediction of melanoma OS, independent of IT. Our analysis revealed that patients with high TMB, high levels of IFNγRes and MacReg had significantly more favorable OS compared to high TMB patients with low IFNγRes and low MacReg. These findings may substantially improve current melanoma prognostic models.

Imaging response to immune checkpoint inhibitors in patients with advanced melanoma: a retrospective observational cohort study

“…Additionally, low sample size may have contributed to this finding. As an example, utilizing the objective response rate of 45% for nivolumab monotherapy and 58% for ipilimumabnivolumab therapies reported in a previous landmark clinical trial (20), a sample size of 462 patients would be required to detect differences at a type II error rate of <0.20. The sample size of this study (n=198) was comparatively modest, possibly accounting for why our results deviate from those reported previously.…”

“…This is especially true if reducing tumour burden is necessary to prolong life and palliate related symptoms. Many different markers, including those focusing on tumour characteristics and other clinical parameters, have been proposed as putative candidate factors (19)(20)(21)(22)(23). However, attempts to discriminate patient populations using these markers are infrequent, with a lack of studies focused on patients with advanced melanoma treated with first-line ICI therapies in a realworld setting (24)(25)(26)(27).…”

Development of a Macrophage-Related Risk Model for Metastatic Melanoma

“…For example, Chen et al constructed a nine-iron-death-associated gene prognostic model, which showed great performance in terms of predicting melanoma prognosis [ 29 ]. Another study constructed an immunogenomic signature prognostic model based on gene expression data derived from TCGA to predict overall survival in melanoma [ 30 ]. A recent study used a six-gene model-based prognostic approach to treat melanoma patients [ 31 ].…”