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18 2024

Analytical and Clinical Validation of a Highly Sensitive NGS-Based ctDNA Assay with Real-World Concordance in NSCLC

ABSTRACT PurposeThere have been needs to improve the sensitivity of liquid biopsy. This report aims to report the analytical and clinical validation of a next generation sequencing (NGS)-based circulating tumor DNA (ctDNA) assay.Materials and MethodsAnalytical validation was conducted in vitro by evaluating the limit of detection (LOD), precision, and specificity for various genomic aberrations. The real-world performance in non-small cell lung cancer (NSCLC) was assessed by comparing the results of AlphaLiquid®100 to the tissue-based results.ResultsThe LODs with 30 ng input DNA were 0.11%, 0.11%, 0.06%, 0.21%, and 2.13 copies for detecting SNVs, insertions, deletions, fusions, and copy number alterations (CNA), respectively. Quantitatively, SNV/INDELs, fusions, and CNAs showed a good correlation (R2=0.91, 0.40, and 0.65; y=0.95, 1.06, and 1.19) to the manufacturer’s values, and per-base specificities for all types of variants were near 100%. In real-world NSCLC (n=122), key actionable mutations in NSCLC were detected in 60.7% (74/122) with the ctDNA assay. Comparative analysis against the NGS-based tissue results for all key mutations showed positive percent agreement (PPA) of 85.3%. For individual genes, the PPA was as high as 95.7% for EGFR mutations and 83.3% for ALK translocations. AlphaLiquid 100 detected drug-sensitive EGFR mutation at a variant allele frequency as low as 0.02% and also identified an EGFR mutation in a case where tissue sample missed. Blood samples collected post-targeted therapies revealed additional acquired mutations.ConclusionThe AlphaLiquid®100 ctDNA assay demonstrates robust analytical validity, offering clinically important information for NSCLC patients.

Cancer Research and Treatment

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17 2023

Mutational evolution after chemotherapy-progression in metastatic colorectal cancer revealed by circulating tumor DNA analysis

Abstract Emerging new mutations after treatment can provide clues to acquired resistant mechanisms. Circulating tumor DNA (ctDNA) sequencing has enabled noninvasive repeated tumor mutational profiling. We aimed to investigate newly emerging mutations in ctDNA after disease progression in metastatic colorectal cancer (mCRC). Blood samples were prospectively collected fr|om mCRC patients receiving palliative chemotherapy before treatment and at radiological evaluations. ctDNA fr|om pretreatment and progressive disease (PD) samples were sequenced with a next-generation sequencing panel targeting 106 genes. A total of 712 samples fr|om 326 patients were analyzed, and 381 pretreatment and PD pairs (163 first-line, 85 second-line and 133 later-line [≥third-line]) were compared. New mutations in PD samples (mean 2.75 mutations/sample) were observed in 49.6% (189/381) of treatments. ctDNA samples fr|om later-line had more baseline mutations (P = .002) and were more likely to have new PD mutations (adjusted odds ratio [OR] 2.27, 95% confidence interval [CI]: 1.40-3.69) compared to first-line. RAS/BRAF wild-type tumors were more likely to develop PD mutations (adjusted OR 1.87, 95% CI: 1.22-2.87), independent of cetuximab treatment. The majority of new PD mutations (68.5%) were minor clones, suggesting an increasing clonal heterogeneity after treatment. Pathways involved by PD mutations differed by the treatment received: MAPK cascade (Gene Ontology [GO]: 0000165) in cetuximab and regulation of kinase activity (GO: 0043549) in regorafenib. The number of mutations revealed by ctDNA sequencing increased during disease progression in mCRC. Clonal heterogeneity increased after chemotherapy progression, and pathways involved were affected by chemotherapy regimens.

International Journal of Cancer

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16 2023 Experimental & Molecular Medicine

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15 2023

Personalised circulating tumour DNA assay with large-scale mutation coverage for sensitive minimal residual disease detection in colorectal cancer

Abstract Background Postoperative minimal residual disease (MRD) detection using circulating-tumour DNA (ctDNA) requires a highly sensitive analysis platform. We have developed a tumour-informed, hybrid-capture ctDNA sequencing MRD assay. Methods Personalised target-capture panels for ctDNA detection were designed using individual variants identified in tumour whole-exome sequencing of each patient. MRD status was determined using ultra-high-depth sequencing data of plasma cell-free DNA. The MRD positivity and its association with clinical outcome were analysed in Stage II or III colorectal cancer (CRC). Results In 98 CRC patients, personalised panels for ctDNA sequencing were built fr|om tumour data, including a median of 185 variants per patient. In silico simulation showed that increasing the number of target variants increases MRD detection sensitivity in low fractions (<0.01%). At postoperative 3-week, 21.4% of patients were positive for MRD by ctDNA. Postoperative positive MRD was strongly associated with poor disease-free survival (DFS) (adjusted hazard ratio 8.40, 95% confidence interval 3.49–20.2). Patients with a negative conversion of MRD after adjuvant therapy showed significantly better DFS (P < 0.001). Conclusion Tumour-informed, hybrid-capture-based ctDNA assay monitoring a large number of patient-specific mutations is a sensitive strategy for MRD detection to predict recurrence in CRC.

British Journal of Cancer

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14 2023 Cancers

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