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Counting how many mutations a tumour carries per stretch of DNA; heavily mutated tumours are more likely to respond to immunotherapy.
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.
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.
The FDA-approved tissue (324 genes) and blood genomic tests that serve as companion diagnostics for dozens of drugs.
Pembrolizumab is a PD-1 blocking antibody approved in more than 40 settings, from melanoma and lung cancer to the first tumour-agnostic approval for mismatch-repair-deficient tumours in 2017, and before and after surgery in triple-negative breast cancer. A subcutaneous form arrived in 2025, and it is the backbone partner for ADCs and personalised neoantigen vaccines.
It is the positive half of the tumour mutational burden story and it applies only to single-agent immunotherapy, which is the setting fewest patients are treated in.
This is the result that ended tumour mutational burden as a practical selector in lung cancer: in the regimen most patients receive, it selects nobody, and neither do the co-mutations most often quoted as reasons to withhold immunotherapy.
It is the strongest case that mutation burden is real biology in lung cancer and, at the same time, the clearest demonstration that its threshold is not fixed, which is why it never became a reliable selector.
TMB-high is uncommon but not negligible in TNBC, rises at relapse, and the tumour-agnostic pembrolizumab indication makes it worth measuring on a metastatic biopsy.
It fixed the working numbers for a comprehensive panel in pancreatic cancer: a hit worth acting on in about one patient in six, most of it in repair genes and the KRAS wild-type minority.
It answered the tissue-exhaustion problem for one biomarker, and in doing so added a third unit to a measurement that already had two, which is part of why the field never converged on a threshold.
It made tumour mutational burden measurable in routine practice and, in the same stroke, showed it is a second axis alongside PD-L1 rather than a replacement for it.
This is the paper Europe PMC returns for registry id NCT02477826 with the most citations, so it is the natural first reading for anyone following the CheckMate 227 trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand.
Query for this technology: (TITLE:"Tumour mutational burden testing" OR ABSTRACT:"Tumour mutational burden testing") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about Tumour mutational burden testing, not a curated reading list.
Shares Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab, Prevalence and mutational determinants of high tumor mutation burden in breast cancer, Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden, Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer.
Shares Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers, FoundationOne CDx / Liquid CDx, Diagnostics roadmap: stains → gene panels → blood tests that decide treatment, Companion diagnostics.
Shares Diagnostics roadmap: stains → gene panels → blood tests that decide treatment, Companion diagnostics, Comprehensive genomic profiling, Triple-negative breast cancer (TNBC).
Shares FoundationOne CDx / Liquid CDx, Companion diagnostics, Comprehensive genomic profiling, Colorectal cancer.
Shares 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, 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, Non-small-cell lung cancer.
Shares Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer, Tumour mutational burden (TMB), Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Pembrolizumab.
Shares 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, Associations of tissue tumour mutational burden and mutational status with clinical outcomes in KEYNOTE-042, 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, Non-small-cell lung cancer.
Shares Companion diagnostics, Comprehensive genomic profiling, Triple-negative breast cancer (TNBC), Pancreatic ductal adenocarcinoma.
Open-source projects that implement or serve this technology, from OnCo's own catalogue: licence and last activity as the repository reported them on the day of the fetch. Listing is not endorsement; check the licence before reuse and the validation before clinical use.
Turns a tumour's somatic variant calls into an interpreted clinical report: driver annotation, actionability tiers, tumour mutational burden, MSI and mutational signatures.
An R package for estimating tumour mutational burden from panel sequencing with the filters that make results comparable.