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Updated: May 27, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
DNA damage repair gene alterations influence the tumor immune microenvironment in advanced non-small cell lung cancer
Kamya Sankar1, Jacob Mercer2, Ellen B Jaeger2
1Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Purpose:
DNA damage response and repair (DDR) gene alterations contribute to genomic instability and increased tumor immunogenicity, yet their clinical significance in non-small cell lung cancer (NSCLC) remains unclear. Using a large real-world dataset, we evaluated the prevalence of DDR alterations and their relation to the tumor immune microenvironment in metastatic NSCLC.
Experimental Design:
We retrospectively analyzed real-world data from patients with metastatic NSCLC using the Tempus AI database. Tumors were sequenced with Tempus xT DNA and xR RNA assays and classified based on the presence (DDRmt) or absence (DDRwt) of a pathogenic somatic alteration or copy number deletion in a DDR pathway gene. Associations between DDR alterations and immune cell infiltration, PD-L1 immunohistochemistry, tumor mutational burden (TMB), and microsatellite instability (MSI-H) were examined.
Results:
Among 14,127 patients (median age = 67, 49% female), 5,276 (37%) were DDRmt. There was a higher prevalence of current/former smokers in the DDRmt group (86% vs. 82%; p<0.001). DDRmt tumors were more likely to have higher levels of TMB (median: 5.4 vs. 4.6; p<0.001), MSI-H (1.1 % vs. <0.1 %; p<0.001), and infiltrating CD8+ T cells (p=0.003) compared to DDRwt tumors. A lower frequency of macrophages (p<0.001) were observed among DDRmt compared with DDRwt tumors with no difference in PDL1 positivity.
Conclusions:
Among patients with metastatic NSCLC, 37% present with DDRmt tumors characterized by higher TMB, frequency of MSI-H, and changes in immune cell infiltrates. These findings provide insight into the immunogenic landscape of DDR-altered NSCLC and may inform biomarker selection and therapeutic strategies.
Insights
37% of metastatic non-small cell lung cancer (NSCLC) patients have DNA damage response (DDR) alterations. These DDR-altered tumors show increased tumor mutational burden and altered immune cell infiltration, impacting NSCLC immunogenicity.
Area of Science:
- Oncology
- Genomics
- Immunology
Background:
- DNA damage response (DDR) gene alterations are linked to genomic instability and tumor immunogenicity.
- The clinical relevance of DDR alterations in non-small cell lung cancer (NSCLC) is not fully understood.
- Investigating DDR alterations in metastatic NSCLC can provide insights into tumor behavior and treatment strategies.
Purpose of the Study:
- To determine the prevalence of DDR alterations in metastatic NSCLC.
- To examine the relationship between DDR alterations and the tumor immune microenvironment.
- To assess the clinical significance of DDR alterations in NSCLC.
Main Methods:
- Retrospective analysis of real-world data from the Tempus AI database.
- Sequencing of tumors using Tempus xT DNA and xR RNA assays.
- Classification of tumors as DDR-altered (DDRmt) or DDR-wildtype (DDRwt) based on pathogenic alterations.
- Examination of associations between DDR status, tumor mutational burden (TMB), microsatellite instability (MSI-H), and immune cell infiltration (CD8+, macrophages, PD-L1).
Main Results:
- 37% of 14,127 metastatic NSCLC patients had DDRmt tumors.
- DDRmt tumors were more common in current/former smokers.
- DDRmt tumors exhibited higher TMB, MSI-H frequency, and CD8+ T cell infiltration.
- DDRmt tumors showed lower macrophage infiltration, with no difference in PD-L1 positivity.
Conclusions:
- A significant proportion of metastatic NSCLC patients (37%) harbor DDR-altered tumors.
- DDR alterations are associated with a more immunogenic tumor profile, including higher TMB and specific immune cell infiltrates.
- These findings highlight the potential of DDR alterations as biomarkers for NSCLC and may guide therapeutic strategies.
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