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- Tumor-Type-Specific TMB Cutoffs for Improved ICI Outcome Prediction: Large-Scale Analysis with Real-World Targeted NGS Data
- Ha Ra Jun, Ji-Young Lee, Changseon Lee, Sung-Min Chun
- Received August 12, 2025 Accepted September 18, 2025 Published online September 19, 2025
- DOI: https://doi.org/10.4143/crt.2025.860 [Accepted]
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Abstract
PDF - Purpose
Tumor mutational burden (TMB) is a potential biomarker for predicting response to immune checkpoint inhibitors (ICIs). However, its clinical utility is limited by methodological inconsistencies. This study aimed to evaluate the predictive value of TMB for ICI outcomes using next-generation sequencing (NGS) data.
Materials and Methods
We retrospectively analyzed 9,459 patients with cancer who underwent tumor-only targeted NGS. TMB-high (TMB-H) cutoffs were defined using an interquartile range (IQR)-based method and validated by comparing the overall survival (OS) and progression-free survival (PFS) in ICI-treated cohorts against both The Cancer Genome Atlas whole-exome sequencing-derived TMB and the universal 10 mutations per megabase (mut/Mb) cutoff. We also examined programmed cell death-ligand 1 (PD-L1) expression and subclonality to address response heterogeneity.
Results
IQR-based TMB-H was significantly associated with longer PFS in the ICI-treated cohort (hazard ratio (HR)=0.85, 95% confidence interval (CI): 0.73–0.98, p=0.02), NGS before ICI subgroup (HR=0.86, p=0.049), and pre-ICI subgroup (HR=0.80, p=0.03). In contrast, the universal 10 mut/Mb cutoff showed no statistical significance. Subgroup analysis revealed significant PFS benefit in bladder (p=0.014), bowel (p=0.013), and uterine cancers (p=0.006). In lung cancer, patients with both TMB-H and very high PD-L1 expression (≥90%) had the longest PFS (HR=0.64, 95% CI: 0.44–0.93, p=0.021). Among the TMB-H samples, high subclonality was associated with worse OS in non-hypermutated cases (p=0.032).
Conclusion
Real-world TMB cutoffs derived from distribution-based methods offer improved predictive value for ICI outcomes. Integration of the PD-L1 expression and subclonality status further refines the predictive utility of TMB, improving precision in ICI treatment.
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- Validation and Clinical Application of ONCOaccuPanel for Targeted Next-Generation Sequencing of Solid Tumors
- Moonsik Kim, Changseon Lee, Juyeon Hong, Juhee Kim, Ji Yun Jeong, Nora Jee-Young Park, Ji-Eun Kim, Ji Young Park
- Cancer Res Treat. 2023;55(2):429-441. Published online November 25, 2022
- DOI: https://doi.org/10.4143/crt.2022.891
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Abstract
PDF
Supplementary Material
PubReader
ePub - Purpose
Targeted next-generation sequencing (NGS) is widely used for simultaneously detecting clinically informative genetic alterations in a single assay. Its application in clinical settings requires the validation of NGS gene panels. In this study, we aimed to validate a targeted hybridization capture-based DNA panel (ONCOaccuPanel) using the Illumina MiSeq sequencing platform. The panel allows the simultaneous detection of single-nucleotide variants (SNVs), insertions, deletions, and copy number changes of 323 genes and fusions of 17 genes in solid tumors.
Materials and Methods
We used 16 formalin-fixed paraffin-embedded (FFPE) tumor samples with previously known genetic mutations and one reference material (HD827) for validation. Moreover, we sequenced an additional 117 FFPE tumor samples to demonstrate the clinical utility of this panel.
Results
Validation revealed a 100% positive percentage agreement and positive predictive value for the detection of SNVs, insertions, deletions, copy number changes, fusion genes, and microsatellite instability–high types. We observed high levels of reproducibility and repeatability (R2 correlation coefficients=0.96-0.98). In the limit of detection assessment, we identified all clinically relevant genes with allele frequencies > 3%. Furthermore, the clinical application of ONCOaccuPanel using 117 FFPE samples demonstrated robust detection of oncogenic alterations. Oncogenic alterations and targetable genetic alterations were detected in 98.2% and 27.4% cases, respectively.
Conclusion
ONCOaccuPanel demonstrated high analytical sensitivity, reproducibility, and repeatability and is feasible for the detection of clinically relevant mutations in clinical settings. -
Citations
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- Risk prediction criteria for the primary hepatic perivascular epithelioid cell tumour family, including angiomyolipoma: analysis of 132 cases with a literature review
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