Titre
Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic.
Type
synthèse (review)
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Chan, T.A.
Auteure/Auteur
Yarchoan, M.
Auteure/Auteur
Jaffee, E.
Auteure/Auteur
Swanton, C.
Auteure/Auteur
Quezada, S.A.
Auteure/Auteur
Stenzinger, A.
Auteure/Auteur
Peters, S.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1569-8041
Statut éditorial
Publié
Date de publication
2019-01-01
Volume
30
Numéro
1
Première page
44
Dernière page/numéro d’article
56
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Résumé
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.
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.
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.
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.
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.
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.
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.
PID Serval
serval:BIB_352758F0496B
PMID
Open Access
Oui
Date de création
2018-11-13T11:52:50.652Z
Date de création dans IRIS
2025-05-20T15:02:03Z
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Nom
30395155_BIB_352758F0496B.pdf
Version du manuscrit
published
Licence
https://creativecommons.org/licenses/by-nc/4.0
Taille
649.71 KB
Format
Adobe PDF
PID Serval
serval:BIB_352758F0496B.P001
URN
urn:nbn:ch:serval-BIB_352758F0496B9
Somme de contrôle
(MD5):a64a0a84ee04bd41f527e7f1269b7ca8