Association of tumor mutational burden and tumor-infiltrating lymphocytes with second primary cancer after complete resection of non-small cell lung cancer.

Introduction: The risk of developing second primary cancers (SPC) after complete surgical resection of non-small cell lung cancer (NSCLC) has been estimated at 1-2% per patient-year. We investigated whether tumor genomic instability, assessed by tumor mutational burden (TMB), and host immune response, assessed by tumor-infiltrating lymphocytes (TILs), were associated with the development of SPC. Methods: Data from three randomized trials included in the Lung Adjuvant Cisplatin Evaluation-Biomarker (LACE-Bio) meta-analysis were used. TMB and TILs were assessed on FFPE specimens. TMB was categorized into tertiles (high >7.8 mutations/MB, moderate >4 to ≤7.8 mutations/MB, and low ≤4 mutations/MB), and TILs were classified as marked vs. other. Associations between biomarkers and competing endpoints (SPC, and death without developing SPC) were evaluated using Fine and Gray sub-distribution hazard models, stratified by trial and adjusted for treatment, age, sex, tumor stage, nodal stage, histology, performance status, and surgery type. Results: TMB and TILs assessments were available for 879 patients with complete clinical covariates. Marked TILs was observed in 85 patients. During follow-up, 47 SPCs and 392 deaths without SPC were observed. No clear association was found between TMB or TILs and the cumulative incidence of SPC. In contrast, low TMB was associated with a higher cumulative incidence of death without SPC compared with moderate TMB (multivariable subdistribution hazard ratio (sHR) = 1.35 [95% confidence interval (CI), 1.06-1.72], p = 0.02). Marked TILs was associated with a lower cumulative incidence of death without SPC, although this association did not reach statistical significance after adjustment (multivariable sHR = 0.71 [95% CI, 0.46-1.10], p = 0.12). Conclusion: This study is the first to evaluate associations between tumor genomic instability and host immune response, and competing endpoints of SPC and death without SPC in patients with completely resected NSCLC. No strong association was observed with SPC, whereas low TMB (compared with moderate TMB) was associated with the competing endpoint of death without developing SPC. Given the limited number of SPC events, these findings require confirmation in larger, independent cohorts of patients with early-stage lung cancer.