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Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Analytical and clinical validation of a NGS panel in detecting targetable variants from ctDNA of metastatic NSCLC
Feifei Fan1, Guozhong Jiang2, Juan Lv3
1Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Background:
Circulating tumor DNA (ctDNA) has emerged as a promising biomarker for noninvasive cancer diagnostics, particularly in the context of metastatic non-small-cell lung cancer (NSCLC). Detecting targetable variants through ctDNA analysis offers the potential to guide treatment decisions, especially in cases where tissue samples are insufficient or unavailable.
Method:
In this study, we developed and validated a next-generation sequencing panel targeting 101 cancer-related genes (101-test) to detect somatic variants in ctDNA from a large cohort of Chinese patients with metastatic NSCLC. The performance of the 101-test was assessed by evaluating its limit of detection (LOD), accuracy, and precision in identifying molecular variants. Additionally, the concordance between ctDNA and tissue samples for detecting targetable variants was analyzed in 904 patients.
Results:
The 101-test demonstrated a LOD of 0.38% for single-nucleotide variants (SNVs), 0.33% for insertions and deletions (InDels), and 0.33% for fusions. Sensitivity was 98.3% for SNVs, 100% for InDels, and 100% for fusions when compared to digital droplet PCR (ddPCR)/breakpoint PCR reference methods. The by-variant sensitivity for somatic variants was 97.5%, with a specificity of 99.9% between tumor-only and tumor-normal analyses. In a real-world cohort, the concordance between ctDNA and tissue samples for identifying targetable variants was 72.2% (457/633). Notably, the EGFR S768I variant, recently recommended by clinical guidelines, achieved an 80% concordance rate. Furthermore, 4.3% of patients (27/633) with targetable variants were identified exclusively through ctDNA testing.
Conclusion:
The ctDNA-based 101-test is a highly sensitive and specific tool for detecting targetable variants in metastatic NSCLC, particularly in cases with insufficient tissue samples. The findings support the use of ctDNA testing as a reliable and complementary method to traditional tissue-based molecular analysis, enhancing the precision of treatment strategies for NSCLC patients.
Insights
A new 101-gene next-generation sequencing test accurately detects circulating tumor DNA (ctDNA) variants in metastatic non-small-cell lung cancer (NSCLC). This ctDNA test complements tissue analysis and identifies targetable mutations, improving NSCLC treatment strategies.
Area of Science:
- Oncology
- Molecular Diagnostics
- Genomics
Background:
- Circulating tumor DNA (ctDNA) is a promising noninvasive biomarker for metastatic non-small-cell lung cancer (NSCLC).
- ctDNA analysis can guide treatment by detecting targetable variants, especially when tissue samples are limited.
Purpose of the Study:
- To develop and validate a next-generation sequencing (NGS) panel (101-test) for detecting somatic variants in ctDNA.
- To assess the performance of the 101-test in a large cohort of Chinese patients with metastatic NSCLC.
- To analyze the concordance between ctDNA and tissue samples for identifying targetable variants.
Main Methods:
- Developed and validated an NGS panel targeting 101 cancer-related genes (101-test).
- Assessed the test's limit of detection (LOD), accuracy, and precision.
- Analyzed concordance between ctDNA and tissue samples in 904 metastatic NSCLC patients.
Main Results:
- The 101-test showed high sensitivity (98.3% for SNVs, 100% for InDels/fusions) and specificity (99.9%).
- Concordance between ctDNA and tissue for targetable variants was 72.2% in a real-world cohort.
- ctDNA testing uniquely identified targetable variants in 4.3% of patients, including the EGFR S768I variant.
Conclusions:
- The ctDNA-based 101-test is a sensitive and specific tool for detecting targetable variants in metastatic NSCLC.
- This ctDNA test is valuable for patients with insufficient tissue samples, complementing traditional methods.
- The findings support using ctDNA testing to enhance precision treatment strategies for NSCLC patients.
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