A Systematic Review and Meta-Analysis of the Impact of Tumour Mutation Burden on Survival Outcomes in Solid Tumours
Meng, A.; Yuile, A.; Sim, H.-w.; Thavaneswaran, S.; Noor, H.; Yeung, J.; Mehta, A.; Powell, J.; Zaman, A.
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BackgroundTumour mutation burden (TMB) is an emerging pan-cancer biomarker with potential predictive value for immune checkpoint inhibitor (ICI) therapy outcomes. However, its prognostic significance remains inconsistent due to methodological variability and differing cut-off thresholds. This systematic review and meta-analysis evaluated the impact of TMB on overall survival (OS) and progression-free survival (PFS) across solid tumours. MethodsFollowing PRISMA 2020 guidelines, we systematically searched PubMed, Scopus, ScienceDirect, and Cochrane databases for studies published between 2010 and 2024. Eligible studies reported hazard ratios (HRs) and 95% confidence intervals (CIs) comparing OS and PFS in high versus low TMB cohorts. Heterogeneity was assessed using the I{superscript 2} statistic, and publication bias via funnel plots and Eggers test. ResultsA total of 5,278 patients across 28 studies were analysed. High TMB was significantly associated with improved OS and PFS, particularly in non-small cell lung cancer (OS: HR = 0.56), gastrointestinal cancers (OS: HR = 0.36), and advanced/recurrent tumours (OS: HR = 0.52). Survival benefits were most pronounced in ICI-treated patients, especially those receiving combination anti-PD-L1/PD-1 and anti-CTLA4 therapy (OS: HR = 0.47; PFS: HR = 0.50). Ultra-high TMB cases had superior outcomes (OS: HR = 0.44) compared to a universal 10 mut/Mb cut-off (OS: HR = 0.58). Variability in TMB measurement across sequencing platforms highlights the need for standardisation. ConclusionHigh TMB is a strong prognostic and predictive biomarker in ICI-treated cancers, yet methodological inconsistencies hinder clinical implementation. Standardising TMB assessment and refining clinically relevant thresholds are essential for optimising its role in precision oncology. PROSPERO registration numberThe protocol of this systematic review is registered on PROSPERO (CRD42024608809).
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