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Cited by 2,683Cancer Immunotherapy and BiomarkersCancer Genomics and DiagnosticsImmunotherapy and Immune Responses

Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic

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Chan, T.A., Yarchoan, M., Jaffee, E., Swanton, C., Quezada, S.A., Stenzinger, A., Peters, S.·2019·Annals of Oncology
DOI 10.1093/annonc/mdy495PMC PMC6336005
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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.

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  • Existing predictive biomarkers (PD-L1 expression, TMB, microsatellite instability, and mismatch repair deficiency) have clinical utility in specific contexts, but their predictive accuracy varies considerably across tumor histologies and patient populations.

    “While these markers have clinical utility in specific contexts, their predictive accuracy varies considerably across tumor histologies and patient populations.”

    From PathTIGR: A pathway topology-informed graph representation learning framework for immunotherapy response prediction (2026) · cites this paper as [15]

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Authors
Chan, T. A., Yarchoan, M., Jaffee, E., Swanton, C., Quezada, S. A., Stenzinger, A., & Peters, S.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • Johns Hopkins University (US)
  • The Francis Crick Institute (GB)
  • University College London (GB)
  • University Hospital Heidelberg (DE)
  • Centre Hospitalier Universitaire Vaudois (CH)
Corresponding author
  • Chan, T.A.
  • Peters, S.
ORCID
Venue
Annals of Oncology
Publisher
Elsevier BV
Published
2019-01
Volume
30
Issue
1
Pages
44-56
ISSN
0923-7534 (ISSN-L)
DOI
10.1093/annonc/mdy495
PMC
PMC6336005
OpenAlex
W2900082702
Cited by
2,683
References
110
Citations by year
2026: 134 · 2025: 265 · 2024: 403 · 2023: 517 · 2022: 604 · 2021: 382 · 2020: 268 · 2019: 106 · 2018: 2
FWCI
20.25
Type
journal article
Language
en
Open access
Licence
Locations
  • Annals of Oncology (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • SERVAL (Université de Lausanne) (publishedVersion, cc-by-nc)
  • IRIS (submittedVersion, cc-by-nc)
  • UCL Discovery (University College London) (submittedVersion)
  • Figshare (submittedVersion, cc-by-nc)
Funders
  • NIH (R35 CA232097)
  • NCI Cancer Center Support (P30 CA008748)
  • Mellnikoff Precision Immunotherapy Kidney Cancer Fund
  • Exelixis, Merck, and Bristol-Myers Squibb
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
tumor mutational burden, immune checkpoint blockade, predictive biomarkers, PD-L1 expression, anti-PD-1, anti-CTLA-4, somatic mutations, lung cancer, bladder cancer, head and neck cancer, targeted panel sequencing
MeSH terms
Antineoplastic Agents, Immunological, Humans, Immunotherapy, Mutation, Neoplasms, Prognosis, Biomarkers, Tumor

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