{"entity":{"id":"paper-mcgrail-tmb-pan-cancer-response-ann-oncol-2021","kind":"paper","name":"High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types","aka":[],"tldr":"Pooling more than 10,000 tumours, a high mutation count predicted response to immunotherapy in melanoma, lung and bladder cancers but not in breast, prostate or brain tumours.","summary":"The authors used data from more than 10,000 tumours in The Cancer Genome Atlas to compare ways of measuring tumour mutational burden and to test whether predicted neoantigen load correlated with CD8 T cells in each cancer type, then analysed checkpoint inhibitor outcomes by objective response (1,551 patients) and overall survival (1,936 patients).\n\nIn cancer types where CD8 T-cell levels rose with neoantigen load, such as melanoma, lung and bladder cancers, high-TMB tumours responded 39.8 per cent of the time (95 per cent confidence interval 34.9 to 44.8), significantly more than low-TMB tumours (odds ratio 4.1). In cancer types with no such relationship, such as breast cancer, prostate cancer and glioma, high-TMB tumours responded 15.3 per cent of the time (9.2 to 23.4) and significantly less often than low-TMB tumours (odds ratio 0.46). Overall survival and continuous TMB gave equivalent results. The authors concluded that their analysis did not support high TMB as a biomarker for checkpoint inhibitors in all solid cancer types.","asOf":"2026-10-20","links":[{"label":"McGrail et al., Ann Oncol 2021","url":"https://doi.org/10.1016/j.annonc.2021.02.006"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/33736924/"}],"tags":["precision"],"related":[],"cancers":[],"sections":["diagnostics"],"technologies":["tmb-testing"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["tmb","tumour-agnostic"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["annals-of-oncology"],"dependsOn":[],"notes":[],"journal":"Annals of Oncology","year":2021,"doi":"10.1016/j.annonc.2021.02.006","pmid":"33736924","authors":"McGrail DJ, Pilié PG, Rashid NU, et al.","paperType":"translational","findings":["Melanoma, lung, bladder and similar cancers: response rate 39.8 per cent in high-TMB tumours, odds ratio 4.1 against low-TMB.","Breast, prostate, glioma and similar cancers: response rate 15.3 per cent in high-TMB tumours, odds ratio 0.46 against low-TMB.","The same pattern held for overall survival and for TMB treated as a continuous measure."],"whatItMeans":"A single tumour-agnostic cut-off assumes a high mutation count means the same thing everywhere. This analysis found it does not, which is why a high count in a breast or prostate cancer is weaker evidence than the same count in a lung cancer.","caveats":["Retrospective pooling of cohorts treated with different checkpoint inhibitors at different times.","Cancer types were grouped by a correlation the authors derived, not by a prespecified rule."],"participants":1936},"route":"/key-papers/paper-mcgrail-tmb-pan-cancer-response-ann-oncol-2021/","neighbours":{"section":[{"id":"diagnostics","kind":"section","name":"Diagnostics & Biomarkers","route":"/fronts/diagnostics/"}],"technology":[{"id":"tmb-testing","kind":"technology","name":"Tumour mutational burden testing","route":"/technologies/tmb-testing/"}],"term":[{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"},{"id":"tumour-agnostic","kind":"term","name":"Tumour-agnostic (tissue-agnostic) approval","route":"/terms/tumour-agnostic/"}],"journal":[{"id":"annals-of-oncology","kind":"journal","name":"Annals of Oncology","route":"/journals/annals-of-oncology/"}]}}