Higher Blood-to-Tissue Tumor Mutational Burden Ratio Is Associated With Poorer Overall Survival in Advanced Non-Small Cell Lung Cancer
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Introduction
Blood-based and tissue-based tumor mutational burden (bTMB and tTMB) show only moderate concordance in advanced non-small cell lung cancer (NSCLC). We hypothesized that discordance between the two measures reflects tumor heterogeneity and carries prognostic information beyond either measure alone.
Methods
We retrospectively identified 105 patients with advanced NSCLC who underwent both blood-based (Guardant360) and tissue-based next-generation sequencing between October 2020 and September 2024. A blood-to-tissue TMB ratio was defined as ln(1+bTMB) − ln(1+tTMB). Multivariable Cox proportional hazards models estimated associations with overall survival (OS) and progression-free survival (PFS), adjusted for age, sex, ECOG performance status, smoking history, histology, and line of therapy.
Results
Median follow-up was 32 months (66 deaths, 83 progression events). A higher blood-to-tissue TMB ratio was independently associated with shorter OS (HR per 1-unit increase 1.60, 95% CI 1.10–2.31; p=0.01) but not PFS (HR 1.07; p=0.67). Neither component was independently prognostic when modeled alone, whereas in a joint model ln(1+bTMB) and ln(1+tTMB) were associated with survival in opposite directions. The ratio remained associated with OS after adjustment for the highest variant allele frequency, radiographic tumor burden, and extrathoracic metastatic organ count, and was uncorrelated with each of these measures. The poorest OS occurred in the discordant High bTMB/Low tTMB group (HR 2.97, 95% CI 1.32–6.66).
Conclusions
Blood-to-tissue TMB discordance was independently associated with shorter overall survival, independent of ctDNA shedding and baseline disease extent. Validation in prospective cohorts with contemporaneous sampling is required.
