A 10-pathway burden score complements tumor mutational burden for outcome stratification in non-small cell lung cancer.

Background: Tumor mutational burden (TMB) summarizes the number of nonsilent mutations in a tumor but does not show whether these alterations cluster within a small set of pathways or extend across several oncogenic programs. To address this distinction, we developed a 10-pathway burden (10-PB) framework and defined the 10-PB score as the number of altered canonical oncogenic pathways per tumor. We then evaluated whether this mutation-based measure of pathway breadth provides information complementary to TMB in non-small cell lung cancer (NSCLC). Methods: Nonsilent mutations were mapped to 10 canonical oncogenic pathways to construct the 10-PB score. We first described pathway-level alteration patterns and then examined associations of 10-PB with survival and treatment response. Its incremental value relative to TMB was assessed using multivariable models, likelihood-ratio tests, and Akaike information criterion. Bootstrap resampling, continuous-risk analyses, and leave-one-pathway-out models were used to evaluate the stability and endpoint-specific structure of the findings. External MSK-based cohorts were used for validation. Results: Most tumors showed alterations in 2-4 pathways, indicating that multi-pathway involvement is common in NSCLC. LUAD and LUSC showed distinct pathway-level profiles. Higher 10-PB was associated with shorter overall survival and progression-free survival after adjustment for clinicopathologic factors and TMB. Model comparisons suggested that 10-PB adds prognostic information to TMB-based models. In the treatment-response analysis, higher 10-PB showed an exploratory association with unfavorable response. Leave-one-pathway-out analyses suggested endpoint-specific patterns, with NOTCH more closely associated with progression-free survival and adverse response, and TGF-β and PI3K more closely associated with overall survival. External cohorts showed broadly consistent results. Conclusion: The 10-PB framework extends mutation-based assessment of NSCLC by describing how broadly nonsilent mutations involve canonical oncogenic pathways. This pathway-breadth measure complements TMB and may help refine prognosis-oriented stratification, while its treatment-response associations should be viewed as exploratory. Prospective validation and integration with functional pathway-activity data are needed before clinical application.