# Tumour mutational burden testing

Source: https://onco.cc/technologies/tmb-testing/  
OnCo record `tmb-testing` (Technology). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Counting how many mutations a tumour carries per stretch of DNA; heavily mutated tumours are more likely to respond to immunotherapy.

## Summary

Tumour mutational burden is reported by comprehensive genomic profiling panels as mutations per megabase. In June 2020 the FDA granted pembrolizumab a tissue-agnostic accelerated approval for unresectable or metastatic solid tumours with TMB of at least 10 mutations per megabase, as measured by FoundationOne CDx, based on the KEYNOTE-158 study. The threshold is contested: panel size, the inclusion of synonymous variants and germline filtering all shift the number, and the Friends of Cancer Research TMB Harmonization Project showed that different panels can disagree around the cut-off. Blood TMB from liquid biopsy panels is an emerging alternative when tissue is inadequate. TMB is most useful in cancers where PD-L1 and MSI do not explain response, such as some sarcomas and rare tumours.

## Fields

- Kind: Technology
- Status: established
- Last checked: 2026-09-10
- Principle: Somatic non-synonymous mutations across the panel's coding territory are counted and normalised to the sequenced megabases, after filtering germline and known driver variants.
- Strengths: Adds a route to immunotherapy for rare cancers; Reported free with every large panel
- Limitations: Panel-dependent values and a debated cut-off; Weak predictive value in some cancers with high TMB such as those driven by tobacco

## Notes

- Lung cancer: the measurement is sound and the threshold is not. Panel estimates track whole-exome estimates at rho 0.86 (Rizvi 2018) and blood-based estimates work without tissue (Gandara 2018), but the three units, mutations per megabase on a panel, mutations per exome on sequencing and a plasma score, are not interchangeable, the data-derived cut in the largest cohort was more than 19 rather than 10 per megabase (Ricciuti 2022), and the whole signal disappears in the chemo-immunotherapy setting where most patients are treated (Garassino 2023).

## Sources

- FDA: pembrolizumab approval for TMB-H solid tumours (2020): https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumors

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- fronts: [Diagnostics & Biomarkers](https://onco.cc/fronts/diagnostics/)
- technologies: [AI scoring of biomarkers and grade on pathology slides](https://onco.cc/technologies/ai-pathology-scoring/), [Companion diagnostics](https://onco.cc/technologies/companion-diagnostic/), [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/)
- drugs: [FoundationOne CDx / Liquid CDx](https://onco.cc/drugs/foundationone-cdx/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [TruSight Oncology Comprehensive](https://onco.cc/drugs/trusight-oncology-comprehensive/)
- terms: [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/), [Tumour mutational burden (TMB)](https://onco.cc/terms/tmb/)
- key papers: [Association of high tumor mutation burden in non-small cell lung cancers with increased immune infiltration and improved clinical outcomes of PD-L1 blockade across PD-L1 expression levels](https://onco.cc/key-papers/paper-ricciuti-tmb-pd-l1-levels-jama-oncol-2022/), [Associations of tissue tumour mutational burden and mutational status with clinical outcomes in KEYNOTE-042](https://onco.cc/key-papers/paper-keynote-042-tmb-mutations-ann-oncol-2023/), [Associations of tissue tumour mutational burden and mutational status with clinical outcomes with pembrolizumab plus chemotherapy versus chemotherapy for metastatic non-small-cell lung cancer](https://onco.cc/key-papers/paper-keynote-189-407-tmb-jtocrr-2023/), [Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab](https://onco.cc/key-papers/paper-gandara-blood-tmb-atezolizumab-nat-med-2018/), [Molecular determinants of response to anti-PD-1 and anti-PD-L1 blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing](https://onco.cc/key-papers/paper-rizvi-targeted-ngs-immunotherapy-determinants-jco-2018/), [Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden](https://onco.cc/key-papers/paper-checkmate-227-n-engl-j-med-2018/), [Prevalence and mutational determinants of high tumor mutation burden in breast cancer](https://onco.cc/key-papers/paper-barroso-sousa-breast-tmb-prevalence-ann-oncol-2020/), [Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers](https://onco.cc/key-papers/paper-singhi-targeted-genome-profiling-3594-pdac-gastroenterology-2019/), [Rizvi 2015: the mutational landscape determines who responds to PD-1 blockade in lung cancer](https://onco.cc/key-papers/paper-rizvi-mutational-landscape-pd1-science-2015/), [Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer](https://onco.cc/key-papers/paper-domingo-somatic-pole-proofreading-colorectal-lancet-gastro-2016/)
- roadmaps: [Diagnostics roadmap: stains → gene panels → blood tests that decide treatment](https://onco.cc/roadmaps/diagnostics-roadmap/)

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