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Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Tumor Mutation Burden and Differentially Mutated Genes Among Immune Phenotypes in Patients with Lung Adenocarcinoma
Hao Wang1,2, Shanhao Chen1, Die Meng1,2
1Department of Medical Oncology, Shanghai Pulmonary Hospital, Shanghai, 200433, People's Republic of China.
Introduction:
Nowadays, immune checkpoint blockades (ICBs) have been extensively applied in non-small cell lung cancer (NSCLC) treatment. However, the outcome of anti-program death-1/program death ligand-1 (anti-PD-1/PD-L1) therapy is not satisfying in EGFR-mutant lung adenocarcinoma (LUAD) patients and its exact mechanisms have not been fully understood. Since tumor mutation burden (TMB) and tumor immune phenotype had been thought as potential predictors for efficacy of ICBs, we further studied the TMB and immune phenotype in LUAD patients to explore potential mechanisms for poor efficacy of ICBs in EGFR positive mutated patients and to find possible factors that could impact the tumor immune phenotype which might uncover some new therapeutic strategies or combination therapies.
Methods:
We enrolled 223 LUAD patients who underwent surgery in our hospital. We evaluated TMB through targeted panel sequencing. The tumor immune phenotype, which could be divided into non-inflamed, intermediate and inflamed, was determined through immunohistochemistry using formalin-fixed paraffin-embedded samples. Enumeration data were analyzed by Chi-square test or Fisher exact test and shown as number (proportion). Logistic regression model was employed for univariate and multivariate analysis of the association between TMB levels and clinical characteristics.
Results:
The median TMB level was 4.0445 mutations/Mb. Multivariate analysis showed the TMB level was significantly associated with age (P=0.026), gender (P=0.041) and EGFR mutation status (P=0.015), and in EGFR-mutant patients we found a lower proportion of patients with mutated KRAS and BRCA2. Furthermore, we found patients with or without metastatic lesions would have different immune phenotype (P=0.007). And the mutational frequencies of ALK, CDKN2A, MAP2K1, IDH2 and PTEN were significantly different among three immune phenotypes.
Conclusion:
Low TMB level could be the reason for the poor efficacy of ICBs in patients having EGFR mutation. And mutational frequencies of KRAS and BRCA2 were lower in EGFR-mutant patients. Furthermore, ALK, CDKN2A, MAP2K1, IDH2 and PTEN might involve in the formation of immune phenotypes.
Insights
Low tumor mutation burden (TMB) may explain the poor response to immune checkpoint blockades (ICBs) in EGFR-mutant lung adenocarcinoma. Specific gene mutations and immune phenotypes are associated with treatment outcomes in these patients.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Immune checkpoint blockades (ICBs) are used for non-small cell lung cancer (NSCLC).
- Anti-program death-1/program death ligand-1 (anti-PD-1/PD-L1) therapy shows limited efficacy in EGFR-mutant lung adenocarcinoma (LUAD).
- Mechanisms underlying poor ICB response in EGFR-mutant LUAD are not fully understood.
Purpose of the Study:
- Investigate tumor mutation burden (TMB) and immune phenotype in LUAD patients.
- Explore mechanisms for poor ICB efficacy in EGFR-mutant LUAD.
- Identify factors impacting tumor immune phenotype for potential new therapeutic strategies.
Main Methods:
- Enrolled 223 LUAD patients undergoing surgery.
- Evaluated TMB using targeted panel sequencing.
- Determined tumor immune phenotype (non-inflamed, intermediate, inflamed) via immunohistochemistry.
- Analyzed associations between TMB, clinical characteristics, and gene mutations using statistical tests and logistic regression.
Main Results:
- Median TMB was 4.0445 mutations/Mb.
- TMB levels significantly correlated with age, gender, and EGFR mutation status.
- EGFR-mutant patients had lower frequencies of KRAS and BRCA2 mutations.
- Metastatic status influenced immune phenotype (P=0.007).
- ALK, CDKN2A, MAP2K1, IDH2, and PTEN mutations differed significantly across immune phenotypes.
Conclusions:
- Low TMB may contribute to the poor efficacy of ICBs in EGFR-mutant LUAD.
- EGFR mutation is associated with lower KRAS and BRCA2 mutation frequencies.
- ALK, CDKN2A, MAP2K1, IDH2, and PTEN may play roles in immune phenotype development.
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