Abstract

Tumor mutational burden (TMB), the total number of somatic coding mutations in a tumor, is emerging as a promising biomarker for immunotherapy response in cancer patients. TMB can be quantitated by a number of NGS-based sequencing technologies. Whole Exome Sequencing (WES) allows comprehensive measurement of TMB and is considered the gold standard. However, to date WES remains confined to research settings, due to high cost of the large genomic space sequenced. In the clinical setting, instead, targeted enrichment panels (gene panels) of various genomic sizes are emerging as the routine technology for TMB assessment. This stimulated the development of various methods for panel-based TMB quantification, and prompted the multiplication of studies assessing whether TMB can be confidently estimated from the smaller genomic space sampled by gene panels. In this review, we inventory the collection of available gene panels tested for this purpose, illustrating their technical specifications and describing their accuracy and clinical value in TMB assessment. Moreover, we highlight how various experimental, platform-related or methodological variables, as well as bioinformatic pipelines, influence panel-based TMB quantification. The lack of harmonization in panel-based TMB quantification, of adequate methods to convert TMB estimates across different panels and of robust predictive cutoffs, currently represents one of the main limitations to adopt TMB as a biomarker in clinical practice. This overview on the heterogeneous landscape of panel-based TMB quantification aims at providing a context to discuss common standards and illustrates the strong need of further validation and consolidation studies for the clinical interpretation of panel-based TMB values.

Highlights

  • Tumor mutational burden (TMB), the total number of somatic coding mutations in a tumor, is emerging as a promising biomarker for immunotherapy response in cancer patients

  • Tumor mutational burden: an emerging biomarker for cancer immunotherapy Immunotherapy with immune checkpoint inhibitors targeting cytotoxic T lymphocyte associated 4 (CTLA-4) or programmed cell death 1 (PD-1) or its ligand (PD-L1) can provide important clinical benefit to patients affected by multiple cancers, most notably lung cancer [1, 2], melanoma [3], renal cancer [4] and urothelial carcinoma [5]

  • Increased TMB was observed in tumors with defects in DNA mismatch repair and DNA replication or in tumors characterized by microsatellite instability, as in colorectal cancer [21, 22]

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Summary

Introduction

Tumor mutational burden (TMB), the total number of somatic coding mutations in a tumor, is emerging as a promising biomarker for immunotherapy response in cancer patients. ORR Objective Response Rates, DCB Durable Clinical Benefit, OS Overall Survival, PFS Progression-Free Survival, FM1 Foundation Medicine’s FoundationOne (v1: 185 genes, v2: 236 genes, v3: 315 genes, v4: 405 genes, Heme: 405 genes, CDx: 324 genes); ±: version not specified; MSK-IMPACT v1 341 genes, v2: 410 genes, v3 468 genes, NSCLC non-small cell lung cancer, ER Estrogen Receptor, VUS variants of unknown significance, PD(L)1 anti-PD-1 or anti-PD-L1, CTLA-4 anti-CTLA-4, combo combined anti-PD-1/PD-L1 + anti-CTLA-4, Q1-Q4 quartiles, a: TMB quantification from blood Each study is described reporting gene panel, cancer type, study design, study ID (on ClinicalTrials.gov), immune checkpoint inhibitor treatment (ICI), proposed TMB cutoff, method for TMB cutoff determination, outcome analyzed to evaluate TMB clinical utility.

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Conclusion

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