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How many mutations a tumour has. More mutations mean more targets for the immune system.
Tumour mutational burden (TMB) counts how many mutations a tumour carries, expressed as mutations per megabase from panel or exome sequencing, on the logic that more mutations mean more targets for the immune system. A TMB of 10 mutations per megabase or higher is a tumour-agnostic indication for Pembrolizumab, established in KEYNOTE-158. It is an imperfect predictor and varies from panel to panel, which is why the idea of a single calibrated TMB across all sequencing panels exists and why the term features in the bottleneck on unvalidated biomarkers. TMB is linked to Comprehensive genomic profiling and Immune checkpoint inhibitors, to the Antigen presentation & immune editing pathway, and to Aurélien Marabelle, Ramaswamy Govindan and Timothy A. Chan.
Backbone ribbon from PDB 5DK3. RCSB PDB 5DK3. The ribbon widens where the chain is folded into a regular pattern and narrows where it is a loose loop.
Showing the molecule this term concerns: Pembrolizumab.
The glossary entry explains the word; the readout page carries the scoring rule, the thresholds approvals use, the companion diagnostics and the tests.
HER2 is as frequent in India as in the West, so HER2 testing pays off in the highest-incidence population, while tumour-agnostic immunotherapy markers will rarely apply. The paper also shows plasma testing is feasible where tissue is scarce.
For the first time a randomised trial suggests that a vaccine tailored to an individual's tumour can reduce relapse when combined with immunotherapy, which is a proof of concept for a field that had failed for decades. Nothing changes for patients yet: the trial was small, the confidence interval crossed one, and the phase 3 trial in melanoma (and parallel trials in lung and other cancers) must confirm it. If it does, personalised mRNA vaccines could become a routine adjunct to checkpoint inhibitors after surgery.
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.
Pancreatic cancer was thought to be immunologically inert because of its low mutation burden; this study showed that with the right vaccine platform its few neoantigens can still be targeted. It is the strongest human evidence so far that personalised cancer vaccines can generate durable, tumour-specific immunity, and it justifies the randomised trials now running in pancreatic cancer and melanoma. Benefit is not yet proven, because responders may simply have had more immunogenic tumours.
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.
This is the fusion and immune-marker table for the wild-type minority, the group in which RNA sequencing pays for itself.
Lung cancer in never-smokers is not smokers' lung cancer with the smoking removed; it is a different set of diseases with a different clock. The slow-growing piano subtype in particular is the argument that a screening test aimed at never-smokers would need to look for something other than what low-dose computed tomography was built to find.
Shares Aurélien Marabelle, Molecular profiling of biliary cancers reveals distinct molecular alterations and potential therapeutic targets, Genomic correlates of immune-cell infiltrates in colorectal carcinoma, Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer.
Shares Integrative molecular characterisation of gallbladder cancer reveals micro-environment-associated subtypes, A standard evolvability score for every tumour, Merkel cell polyomavirus (MCPyV) status, Mutation.
Shares Timothy A. Chan, Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer, Genomic correlates of immune-cell infiltrates in colorectal carcinoma, Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer.
Shares A standard evolvability score for every tumour, A single calibrated tumour mutational burden across all sequencing panels, Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer, The landscape of somatic mutation in normal colorectal epithelial cells.
Shares Molecular profiling of biliary cancers reveals distinct molecular alterations and potential therapeutic targets, Genomic correlates of immune-cell infiltrates in colorectal carcinoma, Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer, Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer.
Shares Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer, Genomic correlates of immune-cell infiltrates in colorectal carcinoma, 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 Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab, CheckMate 026: first-line nivolumab in stage IV or recurrent non-small-cell lung cancer, Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden, 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.
Shares Aurélien Marabelle, CheckMate 026: first-line nivolumab in stage IV or recurrent non-small-cell lung cancer, Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden, Ribas and Wolchok 2018: cancer immunotherapy using checkpoint blockade.