Measuring tumor mutation burden in non-small cell lung cancer: tissue versus liquid biopsy

Fenizia, Francesca; Pasquale, Raffaella; Roma, Cristin; Bergantino, Francesca; Iannaccone, Alessia; Normanno, Nicola

doi:10.21037/tlcr.2018.09.23

Cited by 59 publications

(46 citation statements)

References 47 publications

(66 reference statements)

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“…In addition, the evaluation of tumor mutational burden (TMB), which is the number of somatic mutations in the genome coding regions (Mut/Mb), has been explored and is currently been tested in the cfDNA, to identify patients who can benefit from immunotherapy [99][100][101][102]. However, the first results on the concordance between tissue and cfDNA are contrasting [103]. One of the major issues is the lack of standardization in the TMB evaluation.…”

Section: Discussionmentioning

confidence: 99%

Liquid Biopsy in Non-Small Cell Lung Cancer: Highlights and Challenges

Rijavec

Coco

Genova

et al. 2019

Cancers

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Non-small cell lung cancer is one leading cause of death worldwide, and patients would greatly benefit from an early diagnosis. Since targeted and immunotherapies have emerged as novel approaches for more tailored treatments, repeated assessments of the tumor biology have become pivotal to drive clinical decisions. Currently, tumor tissue biopsy is the gold standard to investigate potentially actionable biomarkers, but this procedure is invasive and may prove inadequate to represent the whole malignancy. In this regard, liquid biopsy represents a minimally invasive and more comprehensive option for early detection and investigation of this tumor. Today, cell-free DNA is the only approved circulating marker to select patients for a targeted therapy. Conversely, the other tumor-derived markers (i.e., circulating tumor cells, miRNAs, exosomes, and tumor educated platelets) are still at a pre-clinical phase, although they show promising results for their application in screening programs or as prognostic/predictive biomarkers. The main challenges for their clinical translation are the lack of reliable cutoffs and, especially for miRNAs, the great variability among the studies. Moreover, no established tool has been approved for circulating tumor cells and exosome isolation. Finally, large prospective clinical trials are mandatory to provide evidence of their clinical utility.

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Section: Discussionmentioning

confidence: 99%

Liquid Biopsy in Non-Small Cell Lung Cancer: Highlights and Challenges

Rijavec

Coco

Genova

et al. 2019

Cancers

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“…TMB has emerged as an independent biomarker to predict patient responses to treatment with ICIs, 18,19,49,50 and the negative predictive role of low TMB could not be overcome by the combination immunotherapy. 50 Several studies have shown to effectively measure TMB from liquid biopsies/blood, [51][52][53][54] this might be an alternative to the biopsies since it is less invasive and easily repeatable. However, TMB assessment by liquid biopsy must face the problem that the circulating DNA deriving from tumor cells is often only a small fraction of the circulating cell free DNA and it needs further investigation and may be clarified within the ongoing clinical trials.…”

Section: Discussionmentioning

confidence: 99%

MiRNA expression patterns are associated with tumor mutational burden in lung adenocarcinoma

Huang

Lin

et al. 2019

OncoImmunology

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Background: Tumor mutational burden (TMB) has emerged as an independent biomarker to predict patient responses to treatment with immune checkpoint inhibitors (ICIs) for lung adenocarcinoma (LUAD). MicroRNAs (miRNAs) have a crucial role in the regulation of anticancer immune responses, but the association of miRNA expression patterns and TMB is not clear in LUAD. Methods: Differentially expressed miRNAs in samples with high TMB and low TMB samples were screened in the LUAD dataset in The Cancer Genome Atlas. The least absolute shrinkage and selection operator (LASSO) method was applied to develop a miRNA-based signature classifier for predicting TMB levels in the training set. An test set was used to validate this classifier. The correlation between the miRNA-based classifier index and the expression of three immune checkpoints (PD-1, PD-L1, and CTLA-4) were explored. Functional enrichment analysis was carried out of the miRNAs included in the miRNAbased signature classifier. Results: Twenty-five differentially expressed miRNAs were used to establish a miRNA-based signature classifier for predicting TMB level. The accuracy of the 25-miRNA-based signature classifier was 0.850 in the training set, 0.810 in the test set and 0.840 in the total set. This miRNA-based signature classifier index showed a low correlation with PD-1 and PD-L1, and no correlation with CTLA-4. Enrichment analysis for these 25 miRNA revealed they are involved in many immune-related biological processes and cancer-related pathways. Conclusion: MiRNA expression patterns are associated with tumor mutational burden and a miRNAbased signature classifier may serve as a biomarker for prediction of TMB levels in LUAD.

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“…Compared with circulating tumor DNA (ctDNA) testing, tissue testing is still the current mainstream method [36]. Blood testing has the advantage of convenient material collection, but the testing technology needs further investigation [37]. In this study, a total of three articles with four studies [26,38,39] used blood samples, and the results were heterogeneous so that no credible conclusions could be drawn about the validity of the blood test results.…”

Section: Discussionmentioning

confidence: 98%

The landscape of tumor mutational burden and its clinical significance in patients with lung cancer: a Multi-omics study with a meta-analysis

Wang

Zhu

Xia

et al. 2020

Preprint

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Background: Current research on tumor mutational burden (TMB) has focused on tumor immunotherapy responsiveness, but the role of TMB in non-immunotherapy patients is unclear. The purpose of this study is to explore the effect of TMB on lung cancer patients in order to clarify and expand the clinical significance of TMB in lung cancer.Methods: We download mutation data of lung cancer cases from The Cancer Genome Atlas (TCGA) database to analyze TMB and its composition, and study the relationship between TMB and clinicopathological characteristics of lung cancer patients. We then systematically retrieved and analyzed studies on the relationship between TMB and survival outcomes. The hazard ratio (HR) and its 95% confidence interval (CI) were used as an effective size to assess the survival outcomes. The subgroup analyses based on the pathological type, treatment method, TMB detection method and detection materials were also performed to explore the factors that might affect the interpretation of TMB results.Results: TMB in lung squamous cell carcinoma is lower than those in lung adenocarcinoma. In lung adenocarcinoma, patients with EGFR mutation have lower TMB than patients with EGFR wild-type. The summary analysis found that TMB is a better prognostic factor in small cell lung cancer, and more evident in small cell lung cancer receiving immunotherapy. TMB is a neutral or poor prognostic indicator in non-small cell lung cancer, but a better prognostic factor in non-small cell lung cancer receiving immunotherapy. In patients with lung adenocarcinoma, including those with EGFR mutation and receiving EGFR-targeted therapies, high TMB means worse survival. TMB detected by blood specimens is inconsistent and unstable compared to TMB detected by tissue. The clinical significance of TMB from blood specimens needs further study on extensive sample data.Conclusions: The pooled results indicated that TMB is a good prognostic factor in lung cancer patients receiving immunotherapy. But high TMB is connected with worse survival in non-small cell lung cancer without receiving immunotherapy, especially in lung adenocarcinoma. For lung adenocarcinoma patients with both EGFR mutation and high TMB, how to make a choice between EGFR-targeted therapy and immunotherapy is still a problem that requires further research.

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Measuring tumor mutation burden in non-small cell lung cancer: tissue versus liquid biopsy

Cited by 59 publications

References 47 publications

Liquid Biopsy in Non-Small Cell Lung Cancer: Highlights and Challenges

Liquid Biopsy in Non-Small Cell Lung Cancer: Highlights and Challenges

MiRNA expression patterns are associated with tumor mutational burden in lung adenocarcinoma

The landscape of tumor mutational burden and its clinical significance in patients with lung cancer: a Multi-omics study with a meta-analysis

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