Development of tumor mutation burden as an immunotherapy biomarker: Utility for the oncology clinic Journal Article


Authors: Chan, T. A.; Yarchoan, M.; Jaffee, E.; Swanton, C.; Quezada, S. A.; Stenzinger, A.; Peters, S.
Article Title: Development of tumor mutation burden as an immunotherapy biomarker: Utility for the oncology clinic
Abstract: Background: Treatment with immune checkpoint blockade (ICB) with agents such as anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) can result in impressive response rates and durable disease remission but only in a subset of patients with cancer. Expression of PD-L1 has demonstrated utility in selecting patients for response to ICB and has proven to be an important biomarker for patient selection. Tumor mutation burden (TMB) is emerging as a potential biomarker. However, refinement of interpretation and contextualization is required. Materials and methods: In this review, we outline the evolution of TMB as a biomarker in oncology, delineate how TMB can be applied in the clinic, discuss current limitations as a diagnostic test, and highlight mechanistic insights unveiled by the study of TMB. We review available data to date studying TMB as a biomarker for response to ICB by tumor type, focusing on studies proposing a threshold for TMB as a predictive biomarker for ICB activity. Results: High TMB consistently selects for benefit with ICB therapy. In lung, bladder and head and neck cancers, the current predictive TMB thresholds proposed approximate 200 non-synonymous somatic mutations by whole exome sequencing (WES). PD-L1 expression influences response to ICB in high TMB tumors with single agent PD-(L) 1 antibodies; however, response may not be dependent on PD-L1 expression in the setting of anti-CTLA4 or anti-PD-1/CTLA-4 combination therapy. Disease-specific TMB thresholds for effective prediction of response in various other malignancies are not well established. Conclusions: TMB, in concert with PD-L1 expression, has been demonstrated to be a useful biomarker for ICB selection across some cancer types; however, further prospective validation studies are required. TMB determination by selected targeted panels has been correlated with WES. Calibration and harmonization will be required for optimal utility and alignment across all platforms currently used internationally. Key challenges will need to be addressed before broader use in different tumor types.
Keywords: mutation; immunotherapy; tumors; human breast; ctla-4 blockade; t-cells; metastatic urothelial carcinoma; landscape; solid; nivolumab; immune checkpoint; cancer; pembrolizumab; pd-1 blockade
Journal Title: Annals of Oncology
Volume: 30
Issue: 1
ISSN: 0923-7534
Publisher: Oxford University Press  
Date Published: 2019-01-01
Start Page: 44
End Page: 56
Language: English
ACCESSION: WOS:000459677700009
DOI: 10.1093/annonc/mdy495
PROVIDER: wos
PMCID: PMC6336005
PUBMED: 30395155
Notes: Review -- Source: Wos
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  1. Timothy Chan
    261 Chan