TMB and TILs show no clear association with second primary cancer in resected NSCLCTumor Markers May Link to Survival in Lung Cancer Patients

Frontiers in Medicine Published September 18, 2026 DOI ↗ Editorial oversight: Dr. Julia Lee, PhD · Oncology, Genomics & Drug Development

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Key Takeaway

Note that TMB and TILs do not show a clear association with the incidence of second primary cancer in resected NSCLC.

This meta-analysis synthesized data from three randomized trials to evaluate the impact of tumor mutational burden (TMB) and tumor-infiltrating lymphocytes (TILs) on outcomes in patients with complete resection of non-small cell lung cancer (NSCLC). The analysis specifically examined the cumulative incidence of second primary cancer (SPC) and death without developing a second primary cancer.

The analysis found no clear association between TMB or TILs and the cumulative incidence of SPC, with 47 SPC events observed. Regarding mortality, low TMB was associated with a higher cumulative incidence of death without SPC compared with moderate TMB (sHR = 1.35; 95% CI, 1.06-1.72; p = 0.02). While marked TILs were associated with a lower cumulative incidence of death without SPC (sHR = 0.71), this finding did not reach statistical significance (95% CI, 0.46-1.10; p = 0.12).

A primary limitation noted by the authors is the limited number of SPC events, which requires confirmation in larger, independent cohorts. This study is the first to evaluate associations between tumor genomic instability, host immune response, and competing endpoints of SPC and death in patients with resected NSCLC. Clinical application is currently limited by the need for larger cohort validation.

How this fits prior evidence

This meta-analysis addresses a gap in the literature by being the first study to evaluate the associations between tumor genomic instability, host immune response, and competing endpoints of second primary cancer and death in patients with resected NSCLC. It does not directly relate to previously covered topics such as paclitaxel resistance, the gut-lung axis, or specific treatments like Ivonescimab, osimertinib, or bispecific antibodies.

Researchers analyzed data from 879 patients who had surgery to remove non-small cell lung cancer. The study looked at two specific markers: tumor mutational burden (TMB) and tumor-infiltrating lymphocytes (TILs). These markers help doctors understand the genetic makeup of a tumor and how the body's immune system responds to the cancer.

The study found that these markers did not show a clear link to the development of a second primary cancer. However, there was a link between lower TMB and a higher risk of death without a second cancer. Additionally, patients with marked TILs showed a lower risk of death without a second cancer, though this specific finding was not statistically significant.

Because the number of second cancer cases was small, these results are not definitive. The findings are based on a meta-analysis of three trials and need to be confirmed by larger studies. Patients should talk to their doctors about how these specific markers might affect their individual treatment plans.

What this means for you:

Certain tumor markers may relate to survival rates in lung cancer patients, but more research is needed.

Common questions

What is the role of TMB and TILs in lung cancer?

TMB measures the amount of mutation in a tumor, while TILs represent the immune cells that enter the tumor. This study looked at how these two factors relate to survival and the development of a second primary cancer in patients who had surgery to remove non-small cell lung cancer.

Did these markers predict a second cancer?

The study found no clear association between TMB or TILs and the occurrence of a second primary cancer. Because there were only 47 cases of second primary cancer observed in the data, researchers say more studies are needed to confirm these specific findings.

How did TMB affect survival outcomes?

The study found that a low TMB was associated with a higher risk of death without a second primary cancer compared to a moderate TMB. This finding was based on a comparison of 879 patients who had their tumors surgically removed.

Study Details

Study typeMeta analysis

EvidenceLevel 1

PublishedSep 2026

View Original Abstract ↓

IntroductionThe 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.MethodsData 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.ResultsTMB 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).ConclusionThis 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.

TMB and TILs show no clear association with second primary cancer in resected NSCLCTumor Markers May Link to Survival in Lung Cancer Patients

How this fits prior evidence

Common questions

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TMB and TILs show no clear association with second primary cancer in resected NSCLCTumor Markers May Link to Survival in Lung Cancer Patients

How this fits prior evidence

Common questions

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