Higher Blood-to-Tissue Tumor Mutational Burden Ratio Is Associated With Poorer Overall Survival in Advanced Non-Small Cell Lung Cancer

Introduction: Tumor mutational burden (TMB) is a biomarker for immune checkpoint inhibitor therapy, traditionally measured in tissue (tTMB). Blood-based TMB (bTMB), derived from circulating tumor DNA, is minimally invasive but shows modest concordance with tTMB. The significance of blood-tissue TMB discordance remains unclear. Methods: We retrospectively analyzed 105 patients with advanced NSCLC who underwent pretreatment blood and tissue next-generation sequencing between October 2020 and September 2024. The blood-to-tissue TMB ratio was defined as ln[(1 + bTMB)/(1 + tTMB)]. Outcomes were overall survival (OS) and progression-free survival (PFS). Survival was assessed using Kaplan-Meier methods and multivariable Cox models. Results: Median follow-up was 10 months. Patients in the lowest ratio tertile had longer OS than those in the upper two tertiles (median, 33 vs 11 months; hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.32-0.97; p = 0.04), whereas PFS did not differ (HR, 0.89; p = 0.62). A higher ratio, analyzed continuously, 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. The association persisted after adjustment for metastatic organ count and radiographic tumor burden. The high-bTMB/low-tTMB subgroup had the poorest OS (HR, 3.17 vs low-bTMB/high-tTMB; p = 0.01). Conclusions: A higher blood-to-tissue TMB ratio was independently associated with worse OS in advanced NSCLC. Directional discordance between bTMB and tTMB may reflect tumor heterogeneity and provide prognostic information beyond either measure alone.