| 31 |
2025 |
Enhanced Detection of Druggable Mutations in Non–Small Cell Lung Cancer Using Targeted Collection of Bronchial Washing Fluid Compared With Plasma and Tumor Tissue
Abstract
PurposeNext-generation sequencing (NGS) has become the gold standard for the molecular testing of patients with non–small cell lung cancer (NSCLC). This prospective study evaluated the performance of NGS using cell-free tumor DNA (ctDNA) extracted fr|om bronchial washing fluid (BWF) collected via a targeted washing technique to detect druggable mutations.
Materials and Methods All study participants simultaneously underwent NGS using three sample types: (1) BWF, (2) plasma, and (3) tumor tissue collected during bronchoscopy. The full patient set (FPS) included all enrolled patients, whereas the analysis intent group (AIG) included patients who underwent successful NGS across all specimen types (BWF, plasma, and tissue).
Results Sixty and 50 patients were included in the FPS and AIG groups, respectively. In FPS, the detection rate of druggable mutations in BWF using NGS was 65%, which was significantly higher than that of plasma (47%) and tissue samples (48%; P 5 .003 and P 5 .002, respectively). In the AIG, the concordance rate for detecting druggable mutations between BWF and tissue samples was 94%. In addition, the detection rate of co-occurring genetic alterations in BWF using NGS was significantly higher than that in plasma samples (92% v 64%, P 5 .001), whereas it was comparable with that in tissue samples (92% v 94%, P 5 1.000). No significant adverse events occurred during the BWF collection.
ConclusionsNGS using ctDNA fr|om BWF obtained through a targeted washing technique is a feasible and reliable method for genomic profiling of NSCLC, providing a promising approach for identifying druggable mutations.
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JCO Precision Oncology |
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| 30 |
2025 |
An open-label, phase IB/II study of abemaciclib with paclitaxel for tumors with CDK4/6 pathway genomic alterations
Abstract
Background
Disruption of cyclin D-dependent kinases (CDKs), particularly CDK4/6, drives cancer cell proliferation via abnormal protein phosphorylation. This open-label, single-arm, phase Ib/II trial evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, combined with paclitaxel against CDK4/6-activated tumors.
Patients and methods
Patients with locally advanced or metastatic solid tumors with CDK4/6 pathway aberrations were included. Based on phase Ib, the recommended phase II doses were determined as abemaciclib 100 mg twice daily and paclitaxel 70 mg/m2 on days 1, 8, and 15, over 4-week-long cycles. The primary endpoint for phase II was the overall response rate (ORR). The secondary endpoints included the clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. Tissue-based next-generation sequencing and exploratory circulating tumor DNA analyses were carried out.
Results
Between February 2021 and April 2022, 30 patients received abemaciclib/paclitaxel (median follow-up: 15.7 months), and 27 were included in the efficacy analysis. CDK4/6 amplification (50%) and CCND1/3 amplification (20%) were common activating mutations. The ORR was 7.4%, with two partial responses, and the CBR was 66.7% (18/27 patients). The median OS and PFS were 9.9 months [95% confidence interval (CI) 5.7-14.0 months] and 3.5 months (95% CI 2.6-4.3 months), respectively. Grade 3 adverse events (50%, 21 events) were mainly hematologic. Genetic analysis revealed a ‘poor genetic status’ subgroup characterized by mutations in key signaling pathways (RAS, Wnt, PI3K, and NOTCH) and/or CCNE amplification, correlating with poorer PFS.
Conclusion
Abemaciclib and paclitaxel showed moderate clinical benefits for CDK4/6-activated tumors. We identified a poor genetic group characterized by bypass signaling pathway activation and/or CCNE amplification, which negatively affected treatment response and survival. Future studies with homogeneous patient groups are required to validate these findings.
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ESMO Open |
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| 29 |
2023 |
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International Journal of Cancer |
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| 28 |
2025 |
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.
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Neoplasia |
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| 27 |
2025 |
Enhanced Detection of Actionable Mutations in NSCLC Through Pleural Effusion Cell-Free DNA Sequencing: A Prospective Study
Abstract
Background: Inadequate tumour samples often hinder
molecular testing in non-small cell lung cancer (NSCLC). Plasma-based cell-free
DNA (cfDNA) sequencing has shown promise in bypassing these tissue limitations.
Nevertheless, pleural effusion (PE) samples may offer a richer cfDNA source for
mutation detection in patients with malignant PE.
Methods: This prospective study enrolled newly
diagnosed advanced NSCLC patients with malignant PE. PE samples were collected
for cfDNA NGS analysis. Meanwhile, PE cell pellet RNA was extracted for reverse
transcription polymerase chain reaction (RT-PCR) for clinically relevant actionable
mutations and then confirmed by Sanger sequencing. The concordance between PE
cell pellet RT-PCR and PE cfDNA NGS analyses was analysed.
Results: Fifty patients were enrolled. The median
age was 68.5 years, and the female-to-male ratio was 29:21. Most patients (74%)
were non-smokers. Notably, 45/50 patients (90%) had actionable mutations,
including EGFR exon 19 deletions (24%), EGFR L858R mutations (36%), HER2 exon20
insertions (10%), ROS1 rearrangements (4%), EGFR exon20 insertions (2%), ALK rearrangements
(4%), RET rearrangements (2%), KRAS G12C mutations (2%), and CD74-NRG1 fusions
(2%). Among the 50 enrolled patients, actionable mutations were detected in 44
(88%) by PE cfDNA NGS, 39 (78%) by PE cell pellet Sanger sequencing, and 33
(66%) by clinical tissue genetic testing (P=0.031). The detection of actionable
mutations fr|om PE cfDNA NGS remained consistently high across M1a to M1c
stages.
Conclusions: PE cfDNA genotyping has clinical
applicability for NSCLC patients and can serve as an additional source for
molecular testing. Incorporating PE NGS cfDNA analysis into genetic testing
enhances diagnostic yield and aids in identifying actionable mutations in
clinical practice.
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European Journal of Cancer |
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