| 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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| 26 |
2024 |
Personalized circulating tumor DNA assay precisely predicts the response of neoadjuvant chemotherapy in breast cancer patients
Abstract
Introduction
Circulating tumor
DNA (ctDNA), which is detected in the blood as cell free DNA fragment fr|om
tumor cells, could indicates genomic landscape, tumor burden and treatment
response during chemotherapy as a non-invasive method. Especially, personized
ctDNA assay by next-generation sequencing(NGS) is able to detect a trace amount
of ctDNA and precisely figure out the change of the amount of ctDNA during NAC
and follow up period after curative surgery. Here, we performed serial ctDNA
evaluations in EBC patients who diagnosed as TNBC or HER2-positive BC and
received NAC followed by curative surgery. We aimed to predict NAC response and
detect minimal residual disease (MRD) using personalized ctDNA assay.
Methods
CtDNA was detected
by AlphaLiquid®Detect,
a tumor-informed personalized MRD detection assay exploring most of the
mutations in tumor. Whole exome
sequencing (WES) of tumor tissue and peripheral blood mononuclear cells (PBMCs)
was performed. Patient-specific somatic mutations were selected using a
proprietary algorithm. In brief, clonal variants were prioritized using
integrated information including variant allele frequency, population allele
frequency databases, somatic variant databases, variant pathogenicity, and
genomic context. Up to 100 variants were selected for patient monitoring. A
hybridization capture panel consisting of a pool of 4 patients’ selected
variants was synthesized. These bespoke panels (BSPs) were used for ctDNA
detection. Patients with more than 2 tumor-derived mutations detected in plasma
were considered as ctDNA positive.
Inclusion criteria
included patient who diagnosed as stage IIA-IIIC BC planned to NAC followed by
curative surgery. Among BC subtypes, TNBC and HER2-positive BC were allowed.
Collection of specimens and associated clinical data used in this study was approved
by the Institutional Review Board of Samsung Medical Center (IRB File
No.2021-02-033), and we received informed consents for this study.
Results
fr|om May 2021 to
Sep 2022, 158 patients has been enrolled. Archival tissues were not available
in 47 patients and tissue WES had failed in six patients. Therefore, 105
patients were enrolled and analyzed their ctDNA at diagnosis based on tissue
WES data.
Of 105 patients,
Median age of BC patients was 49.3 years of age (range: 26.1, 67.8). Thirty-six
patients (34.3%) were post-menopausal status and others (65.7%) were
pre-menopausal status. In BC pathology at diagnosis, 56 (53.3%) were TNBC and
other 49 (46.7%) were HER2-positive BC. Among HER2-positive BC, hormone
receptor (HR)-positive were in 21 (20.0%). In clinical stage at diagnosis,
stage II were 46 (43.8%) and stage III in 59 (56.2%).
In 105 patients,
median number of somatic mutations was 60 (interquartile range [IQR]: 38.5,
91). CtDNA detection rate at BC diagnosis was 90.5% and all of BC which not be
detected ctDNA was HER2-positive BC with clinical stage II. Median amount of
ctDNA at diagnosis was 20 (IQR: 6, 44).
In the number of
somatic mutations, there was no difference according to BC subtypes (P=0.121)
and clinical stage (P=0.700) but the amounts of ctDNA at diagnosis was
different. CtDNA was much more detected in TNBC compared to HER2-positive BC
(Median: 34.5 vs. 15.9; P<0.001) and clinical stage III compared to clinical
stage II (Median 33.2 vs. 19.5; P=0.002). After NAC, ctDNA at curative surgery
was tested in 70 patients. In 70 patients, pathologic complete response(pCR)
was observed in 44 patients. CtDNA was detected in ten patients (14.3%) and
eight did not achieve pCR and two with pCR (Specificity of assay: 95.5%,
positive predictive value: 0.80, P=0.032).
Conclusions
Personalized ctDNA assay can precisely detected ctDNA at diagnosis and
their detection rate was associated with BC subtypes and clinical stage. In
addition, ctDNA at curative surgery also can predict NAC response in EBC
patients. Long term ctDNA follow up of MRD would be warranted.
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Cancer Research |
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