scholarly journals Early identification of disease progression in ALK-rearranged lung cancer using circulating tumor DNA analysis

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Arlou Kristina Angeles ◽  
Petros Christopoulos ◽  
Zhao Yuan ◽  
Simone Bauer ◽  
Florian Janke ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Disease Progression ◽  
Dna Analysis ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Circulating Tumor Dna ◽  
Plasma Dna ◽  
Early Detection Of Disease ◽  
Targeted Next Generation Sequencing ◽  
Longitudinal Plasma

AbstractTargeted kinase inhibitors improve the prognosis of lung cancer patients with ALK alterations (ALK+). However, due to the emergence of acquired resistance and varied clinical trajectories, early detection of disease progression is warranted to guide patient management and therapy decisions. We utilized 343 longitudinal plasma DNA samples from 43 ALK+ NSCLC patients receiving ALK-directed therapies to determine molecular progression based on matched panel-based targeted next-generation sequencing (tNGS), and shallow whole-genome sequencing (sWGS). ALK-related alterations were detected in 22 out of 43 (51%) patients. Among 343 longitudinal plasma samples analyzed, 174 (51%) were ctDNA-positive. ALK variant and fusion kinetics generally reflected the disease course. Evidence for early molecular progression was observed in 19 patients (44%). Detection of ctDNA at therapy baseline indicated shorter times to progression compared to cases without mutations at baseline. In patients who succumbed to the disease, ctDNA levels were highly elevated towards the end of life. Our results demonstrate the potential utility of these NGS assays in the clinical management of ALK+ NSCLC.

scholarly journals Molecular findings reveal possible resistance mechanisms in a patient with ALK-rearranged lung cancer: a case report and literature review

ESMO Open ◽  
2019 ◽  
Vol 4 (5) ◽  
pp. e000561 ◽  
Author(s):  
Anastasia Kougioumtzi ◽  
Panagiotis Ntellas ◽  
Eirini Papadopoulou ◽  
George Nasioulas ◽  
Eleftherios Kampletsas ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Disease Progression ◽  
Kinase Inhibitors ◽  
Wide Spectrum ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Molecular Testing ◽  
Liquid Biopsies ◽  
Disease Biology ◽  
Remarkable Progress

Background: Non-small-cell lung cancer (NSCLC) is recognised as a particularly heterogeneous disease, encompassing a wide spectrum of distinct molecular subtypes. With increased understanding of disease biology and mechanisms of progression, treatment of NSCLC has made remarkable progress in the past two decades. Molecular testing is considered the hallmark for the diagnosis and treatment of NSCLC, with liquid biopsies being more and more often applied in the clinical setting during the recent years. Rearrangement of the ALK gene which results in the generation of fusion oncogenes is a common molecular event in NSCLCs. Among ALK fusion transcripts, EML4-ALK fusion is frequently observed and can be targeted with ALK tyrosine kinase inhibitors (TKI). However, acquired resistance and disease progression in many cases are inevitable.Method: Here, we present the case of a patient with NSCLC treated with TKIs, in which molecular profiling of the tumour was performed with different methods of tissue and plasma testing at each disease progression. A review of the literature was further conducted to offer insights into the resistance mechanisms of ALK-rearranged NSCLC.Conclusions: Based on the results, the EML4-ALK fusion initially detected in tumour tissue was preserved throughout the course of the disease. Two additional ALK mutations were later detected in the tissue and plasma and are likely to have caused resistance to the administered TKIs. Continued research into the mechanisms of acquired resistance is required in order to increase the benefit of the patients treated with targeted ALK TKIs.

scholarly journals Changes in the concentration of EGFR-mutated plasma DNA in the first hours of anti-EGFR therapy allow the prediction of tumor response in patients with EGFR-driven lung cancer

2021 ◽  
Vol 67 (5) ◽  
pp. 665-674
Author(s):  
Aleksandr S Martianov ◽  
Fedor Moiseenko ◽  
Albina Zhabina ◽  
Tatyana Sokolova ◽  
Sergey Beluhin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Disease Control ◽  
Kinase Inhibitors ◽  
Tumor Response ◽  
Objective Response ◽  
Progression Free Survival ◽  
Circulating Tumor Dna ◽  
Plasma Dna ◽  
Egfr Mutant ◽  
Egfr Mutated

This study aimed to analyze changes in the plasma concentration of EGFR-mutated DNA occurring immediately after the start of therapy with EGFR tyrosine kinase inhibitors (TKIs). The study included 30 patients with EGFR mutation-driven non-small cell lung cancer (NSCLC).  Serial plasma samples were collected before intake of the first tablet and at 0.5, 1, 2, 3, 6, 12, 24, 36 and 48 hours after the start of the therapy. EGFR-mutated plasma DNA (EGFR+ ctDNA) was detectable at diagnosis in 25 out of 30 study participants. There were different patterns of changes of the amount of circulating tumor DNA, i.e., the consistent decline of ctDNA content, or continuing increase of the number of circulating EGFR mutant copies, or alternating spikes and drops in the ctDNA concentration. Correlation with the disease outcome was observed only for the measurement performed at 48 hours. Twelve (50%) out of 24 informative patients showed >25% reduction of the ctDNA content at 48 h time point; all these patients demonstrated disease control after 4 and 8-12 weeks of therapy. The remaining 12 individuals showed either stable content of circulating EGFR+ DNA (n = 5) or the elevation of ctDNA concentration (n = 7). 10 of 12 patients with elevated or stable ctDNA level achieved an objective response at 4 weeks, but only 5 of 10 evaluable patients still demonstrated disease control at 8-12 weeks (p = 0.014, when compared to the group with ctDNA decrease). The decline of the amount of circulating EGFR mutant copies also correlated with longer progression-free survival (PFS; 14.7 months vs. 8.5 months, p = 0.013). Conclusion: Monitoring of plasma EGFR-M+ concentration within the first hours of the TKI therapy may be used as an immediate predictor of tumor response to the treatment. 

Predictive and prognostic values of circulating tumor DNA (ctDNA) clearance in osimertinib treated advanced non-small cell lung cancer cohort.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3036-3036 ◽  
Author(s):  
Yong Song ◽  
Shenglin Ma ◽  
Meiqi Shi ◽  
Xingxiang Xu ◽  
Xueqin Chen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Disease Progression ◽  
Clonal Evolution ◽  
Gene Copy Number ◽  
Circulating Tumor Dna ◽  
Allelic Frequency ◽  
Gene Copy ◽  
Early Detection Of Disease ◽  
Molecular Changes

3036 Background: Although growth advantage of certain clones would ultimately translate into a clinically visible disease progression, radiological imaging does not reflect clonal evolution at the molecular level. CtDNA, validated as a tool for mutation detection in lung cancer, reflects dynamic molecular changes. Here, we evaluated the potential of ctDNA in monitoring molecular changes and predicting clinical outcomes of EGFR T790M-positive osimertinib treated NSCLC pts. Methods: This prospective multicenter study, enrolled 72 T790M positive osimertinib-treated advanced NSCLC pts who progressed on prior EGFR-TKI to evaluate the potential of ctDNA in monitoring, is part of the ongoing ASTRIS study (NCT02474355). Longitudinal plasma samples, collected from 52 pts, were subjected to sequencing using a panel consisting of 168 lung cancer-related genes. Results: Genomic profile prior to the initiation of osimertinib revealed that mutations participating in cell cycle (14 pts, p = 0.004) and P53 pathways (43 pts, p = 0.032) were associated with shorter OS ( p53 was excluded from analysis due to high mutation frequency). Interestingly, pts with undetectable ctDNA at first follow-up (within 50 d, n = 41) were correlated with longer PFS (p = 0.009) and OS (p = 0.022). With a median follow-up of 168 d (ranged from 40 - 550 d), 32 pts experienced radiological disease progression. Among them, 11 (34%) experienced molecular progression reflected by emergency of new mutation or increased allelic frequency of existing mutation prior to radiological progression, with an average leading time of 74 days. Pts with molecular PD prior to radiological PD were more likely to harbor any gene copy number amplification (CNA, p = 0.035) and p53 (p = 0.023) mutations at radiological PD. In addition, pts with CNA at radiological PD had shorter PFS (p = 0.002) and OS (p = 0.052). Conclusions: This clinical trial study demonstrates that ctDNA clearance at first follow-up can serve as a predictive and a prognostic marker for pts undergoing osimertinib treatment. Furthermore, it revealed the potential of ctDNA in early detection of disease progression, preceding imaging modalities with an average lead time of 74 days.

scholarly journals Utility of Circulating Tumor DNA for Detection and Monitoring of Endometrial Cancer Recurrence and Progression

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2231
Author(s):  
Esther L. Moss ◽  
Diviya N. Gorsia ◽  
Anna Collins ◽  
Pavandeep Sandhu ◽  
Nalini Foreman ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cancer Recurrence ◽  
Circulating Tumor Dna ◽  
Plasma Dna ◽  
Poor Overall Survival ◽  
Targeted Next Generation Sequencing ◽  
Whole Exome ◽  
Longitudinal Plasma ◽  
Ctdna Analysis ◽  
Tumor Dna

Despite the increasing incidence of endometrial cancer (EC) worldwide and the poor overall survival of patients who recur, no reliable biomarker exists for detecting and monitoring EC recurrence and progression during routine follow-up. Circulating tumor DNA (ctDNA) is a sensitive method for monitoring cancer activity and stratifying patients that are likely to respond to therapy. As a pilot study, we investigated the utility of ctDNA for detecting and monitoring EC recurrence and progression in 13 patients, using targeted next-generation sequencing (tNGS) and personalized ctDNA assays. Using tNGS, at least one somatic mutation at a variant allele frequency (VAF) > 20% was detected in 69% (9/13) of patient tumors. The four patients with no detectable tumor mutations at >20% VAF were whole exome sequenced, with all four harboring mutations in genes not analyzed by tNGS. Analysis of matched and longitudinal plasma DNA revealed earlier detection of EC recurrence and progression and dynamic kinetics of ctDNA levels reflecting treatment response. We also detected acquired high microsatellite instability (MSI-H) in ctDNA from one patient whose primary tumor was MSI stable. Our study suggests that ctDNA analysis could become a useful biomarker for early detection and monitoring of EC recurrence. However, further research is needed to confirm these findings and to explore their potential implications for patient management.

scholarly journals Real-world osimertinib for EGFR mutation-positive non-small-cell lung cancer with acquired T790M mutation

2020 ◽  
Vol 16 (21) ◽  
pp. 1537-1547
Author(s):  
Fumio Imamura ◽  
Madoka Kimura ◽  
Yukihiro Yano ◽  
Masahide Mori ◽  
Hidekazu Suzuki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Acquired Resistance ◽  
Small Cell ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Clinical Trial Registration

Aim: Osimertinib is a key drug for EGFR mutation-positive non-small-cell lung cancer (NSCLC). As the hazards ratio of overall survival in comparison with first-generation EGFR-tyrosine kinase inhibitors was almost similar between FLAURA and ARCHER 1050, salvage use of osimertinib is still a treatment option. Patients & methods: We retrospectively analyzed the clinical courses of EGFR mutation-positive NSCLC patients who were potential candidates for salvage osimertinib. Results: Among 524 patients enrolled from five hospitals, 302 patients underwent biopsy, with 52.6% detection rate of T790M. Osimertinib was administered in 93.6% of the T790M-positive patients. The overall response rate and median progression-free survival time of osimertinib were calculated with 147 patients, to be 55.6% and 17.2 months, respectively. Conclusion: Osimertinib is active for T790M-driven acquired resistance in EGFR-mutant NSCLC, but the detection of T790M was unsatisfactory. Clinical Trial Registration: UMIN000028989 (UMIN Clinical Trials Registry)

scholarly journals Circulating Tumor DNA Analysis during Radiation Therapy for Localized Lung Cancer Predicts Treatment Outcome

2017 ◽  
Vol 99 (2) ◽  
pp. S1-S2 ◽  
Author(s):  
A.A. Chaudhuri ◽  
A.F. Lovejoy ◽  
J.J. Chabon ◽  
A. Newman ◽  
H. Stehr ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Radiation Therapy ◽  
Treatment Outcome ◽  
Dna Analysis ◽  
Circulating Tumor Dna ◽  
Tumor Dna

scholarly journals Tumor immune microenvironment in non-small cell lung cancer with EGFR mutation before and after EGFR-TKIs treatment

2021 ◽  
Author(s):  
chao wang ◽  
lihui liu ◽  
sini li ◽  
hua bai ◽  
jie wang
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Treatment Time ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Before And After ◽  
Almost All ◽  
Egfr Tkis

Lung cancer is the most common cancer and a leading cause of death from cancer in men and women in the world. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are considered as the first-line treatment of EGFR mutated NSCLC. However, almost all patients eventually develop acquired resistance to EGFR-TKIs, with a median PFS of 9-14 months. With the development of immunotherapy, people realize that the interaction between tumor immune microenvironment (TIME) and tumor cells can also affect EGFR-TKIs treatment. TIME contains a variety of elements and previous researches of TIME in EGFR-TKIs therapy on NSCLC are decentralized. Here, we review the characteristics of TIME in NSCLC from EGFR-TKIs therapy and its role in TKIs resistance.

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