| 20 |
2024 |
Concordance of ctDNA and tissue genomic profiling in advanced biliary tract cancer
Abstract
Background
& Aims
Recent advances in
molecular profiling have enabled the identification of potential therapeutic
targets for biliary tract cancer (BTC). However, in patients with BTC,
molecular profiling is hindered by challenges in obtaining adequate tissue
samples. Circulating tumor DNA (ctDNA) may offer an alternative to tissue-based
analysis. Herein, we aimed to assess the concordance between ctDNA and tissue
genomic profiling in a large cohort of Asian patients with advanced BTC, and to
evaluate the feasibility of liquid biopsy in BTC treatment.
Methods
This study
included patients with systemic treatment-naive advanced BTC, treated at CHA
Bundang Medical Center between January 2019 and December 2022. We enrolled
patients with available baseline tissue-based next-generation sequencing, and
sufficient plasma samples for ctDNA analysis (AlphaLiquid®100 fr|om IMBdx).
Results
Among 102 enrolled
patients, 49.0% had intrahepatic cholangiocarcinoma, 26.5% extrahepatic
cholangiocarcinoma, and 24.5% gallbladder cancer. The concordance between
intra-patient ctDNA and tumor tissue mutations revealed a sensitivity of 84.8%,
and positive predictive value of 79.4%. ctDNA revealed targetable alterations
in 34.3% of patients – including FGFR2 fusions, IDH1 mutations, microsatellite
instability-high, ERBB2 amplifications, PIK3CA mutations, BRCA1/2 mutations,
and MET amplifications. Notably, a novel FGFR2-TNS1 fusion was identified in
ctDNA, which was not targeted in the tissue NGS panel. A high maximum somatic
variant allele frequency in ctDNA was associated with poor prognosis after
gemcitabine/cisplatin-based chemotherapy, in terms of both overall survival (p
= 6.9 × 10−6) and progression-free survival (p = 3.8 × 10−7
).
Conclusions
Among patients
with advanced BTC, ctDNA-based genotyping showed acceptable concordance with
tissue genomic profiling. Liquid biopsy using ctDNA could be a valuable
complement to tissue-based genomic analysis in BTC.
|
Journal of Hepatology |
リンクを見る
|
| 19 |
2024 |
Clinical utility and predictive value of cerebrospinal fluid cell-free DNA profiling in non-small cell lung cancer patients with leptomeningeal metastasis
Abstract
Leptomeningeal
metastasis (LM) is a challenging complication of non-small cell lung cancer
(NSCLC). Cerebrospinal fluid (CSF) cell-free DNA (cfDNA) analysis using
next-generation sequencing (NGS) offers insights into resistance mechanisms and
potential treatment strategies. We conducted a study fr|om February 2022 to
April 2023 involving patients fr|om five hospitals in Taiwan who had recurrent
or advanced NSCLC with LM. These patients underwent CSF cfDNA analysis using a
118-gene targeted panel for NGS, with comprehensive clinical data collected.
Among 25 enrolled patients, 22 (88.0 %) had EGFR mutations, while three (12.0
%) had EML4-ALK fusion, KIF5B-RET fusion, and ERBB2 A775_G776insSVMA. CSF cfDNA
sequencing of 27 samples (fr|om 25 patients) all confirmed their original driver
mutations. Of total cohort, 18 patients (72.0 %) underwent intrathecal
pemetrexed (ITP), with a median survival time of 7.4 months (95.0 % confidence
interval, 3.3–11.6) fr|om the initiation of ITP to death. Among them, ten
individuals (55.6 %) survived beyond 6 months. Notably, MET copy number gain
(CNG) correlated significantly with survival time exceeding 6 months after ITP
(p = 0.007). The coexistence of EGFR T790M and EGFR-independent resistance
alterations was associated with shorter survival times after ITP, with a median
survival time of 1.9 months compared to 9.9 months for those without EGFR T790M
(p = 0.010). Our results highlight CSF cfDNA NGS's potential in LM resistance
understanding and ITP efficacy prediction. MET CNG positively impacts survival for
ITP recipients, whereas the coexistence of EGFR T790M and EGFR-independent
resistance mechanisms leads to poor outcomes.
|
Neoplasia |
リンクを見る
|
| 18 |
2024 |
Profiling Cell Free DNA from Malignant Pleural Effusion for Oncogenic Driver Mutations in Patients with Treatment Naive Stage IV Adenocarcinoma: A Multicenter Prospective Study
Abstract
Introduction
Comprehensive next-generation sequencing (NGS) of non-small-cell lung cancer specimens can identify oncogenic driver mutations and their corresponding targeted therapies. Plasma cell-free DNA (cfDNA) genotyping is easy to perform; however, false negatives cannot be overlooked. We explored malignant pleural effusion (MPE), a rich source of cfDNA, as a non-inferior alternative to tumor tissues for genotyping.
Methods
We conducted a prospective trial including 39 patients with newly diagnosed stage IV lung adenocarcinoma who presented with MPE. Tissue tests matching hotspot variants, including EGFR, ALK, and ROS1, were compared with the AlphaLiquid100 of PE-cfDNA.
Results
Among the 39 PE-cfDNA samples successfully sequenced, 32 (82.1%) had a PE cell-block tumor content of < 10%. Standard tissue or cell-block testing for EGFR, ALK, and ROS1 identified 20 mutations (51.3%), whereas PE cfDNA identified 25 mutations (64.1%). Five EGFR mutations were observed in PE cfDNA but not in Cobas EGFR owing to coverage or insufficient tumor content issues. The overall rate of oncogenic mutations identified in the PE cfDNA was 92.3%, and the mutation distribution was as follows: even with a very low cfDNA input, high detection rates could be achieved. Otherwise, most patients harbored co-mutations. Comparison of pleural fluid NGS with traditional testing revealed differences in accuracy. We also followed up with patients with EGFR-sensitizing mutations who had a treatment response rate of 97.2% after 3 months.
Conclusions
Genotyping of MPE supernatant cfDNA is feasible in clinical practice, in addition to plasma and tumor testing, to improve diagnostic yield and extend patients’ benefit fr|om targeted therapies.
|
Molecular Diagnosis & Therapy |
リンクを見る
|
| 17 |
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 |
リンクを見る
|
| 16 |
2023 |
Cancer signature ensemble integrating cfDNA methylation, copy number, and fragmentation facilitates multi-cancer early detection
Abstract
Cell-free DNA (cfDNA) sequencing has demonstrated great potential for early cancer detection. However, most large-scale studies have focused only on either targeted methylation sites or whole-genome sequencing, limiting comprehensive analysis that integrates both epigenetic and genetic signatures. In this study, we present a platform that enables simultaneous analysis of whole-genome methylation, copy number, and fragmentomic patterns of cfDNA in a single assay. Using a total of 950 plasma (361 healthy and 589 cancer) and 240 tissue samples, we demonstrate that a multifeature cancer signature ensemble (CSE) classifier integrating all features outperforms single-feature classifiers. At 95.2% specificity, the cancer detection sensitivity with methylation, copy number, and fragmentomic models was 77.2%, 61.4%, and 60.5%, respectively, but sensitivity was significantly increased to 88.9% with the CSE classifier (p value < 0.0001). For tissue of origin, the CSE classifier enhanced the accuracy beyond the methylation classifier, fr|om 74.3% to 76.4%. Overall, this work proves the utility of a signature ensemble integrating epigenetic and genetic information for accurate cancer detection.
|
Experimental & Molecular Medicine |
リンクを見る
|
