scholarly journals Longitudinal Circulating Tumor DNA Analysis in Blood and Saliva for Prediction of Response to Osimertinib and Disease Progression in EGFR-Mutant Lung Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3342
Author(s):  
Chul Kim ◽  
Liqiang Xi ◽  
Constance M. Cultraro ◽  
Fang Wei ◽  
Gregory Jones ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Dna Analysis ◽  
Early Time ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Tumor Burden ◽  
Egfr Mutant ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Background: We assessed whether serial ctDNA monitoring of plasma and saliva predicts response and resistance to osimertinib in EGFR-mutant lung adenocarcinoma. Three ctDNA technologies—blood-based droplet-digital PCR (ddPCR), next-generation sequencing (NGS), and saliva-based EFIRM liquid biopsy (eLB)—were employed to investigate their complementary roles. Methods: Plasma and saliva samples were collected from patients enrolled in a prospective clinical trial of osimertinib and local ablative therapy upon progression (NCT02759835). Plasma was analyzed by ddPCR and NGS. Saliva was analyzed by eLB. Results: A total of 25 patients were included. We analyzed 534 samples by ddPCR (n = 25), 256 samples by NGS (n = 24) and 371 samples by eLB (n = 22). Among 20 patients who progressed, ctDNA progression predated RECIST 1.1 progression by a median of 118 days (range: 61–272 days) in 11 (55%) patients. Of nine patients without ctDNA progression by ddPCR, two patients had an increase in mutant EGFR by eLB and two patients were found to have ctDNA progression by NGS. Levels of ctDNA measured by ddPCR and NGS at early time points, but not volumetric tumor burden, were associated with PFS. EGFR/ERBB2/MET/KRAS amplifications, EGFR C797S, PIK3CA E545K, PTEN V9del, and CTNNB1 S45P were key resistance mechanisms identified by NGS. Conclusion: Serial assessment of ctDNA in plasma and saliva predicts response and resistance to osimertinib, with each assay having supplementary roles.

scholarly journals Differential Mutation Detection Capability Through Capture-Based Targeted Sequencing in Plasma Samples in Hepatocellular Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Jian Gao ◽  
Lei Xi ◽  
Rentao Yu ◽  
Huailong Xu ◽  
Min Wu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Circulating Tumor Dna ◽  
Tumor Burden ◽  
Targeted Next Generation Sequencing ◽  
Targeted Ngs ◽  
Tumor Protein P53 ◽  
Next Generation Sequencing Ngs ◽  
Coding Variants ◽  
G Protein Coupled ◽  
Generation Sequencing

Circulating tumor DNA (ctDNA) is a promising biomarker for accurate monitoring and less invasive assessment of tumor burden and treatment response. Here, targeted next-generation sequencing (NGS) with a designed gene panel of 176 cancer-relevant genes was used to assess mutations in 90 ctDNA samples from 90 patients with multiple types of liver disease and 10 healthy donor samples for control. Using our ctDNA detection panel, we identified mutations in 98.89% (89/90) of patient plasma biopsy samples, and 19 coding variants located in 10 cancer-related genes [ACVR2A, PCLO, TBCK, adhesion G protein-coupled receptor (ADGRV1), COL1A1, GABBR1, MUC16, MAGEC1, FASLG, and JAK1] were identified in 96.7% of patients (87/90). The 10 top mutated genes were tumor protein p53 (TP53), ACVR2A, ADGRV1, MUC16, TBCK, PCLO, COL11A1, titin (TTN), DNAH9, and GABBR1. TTN and TP53 and TTN and DNAH9 mutations tended to occur together in hepatocellular carcinoma samples. Most importantly, we found that most of those variants were insertions (frameshift insertions) and deletions (frameshift deletions and in-frame deletions), such as insertion variants in ACVR2A, PCLO, and TBCK; such mutations were detected in almost 95% of patients. Our study demonstrated that the targeted NGS-based ctDNA mutation profiling was a useful tool for hepatocellular carcinoma (HCC) monitoring and could potentially be used to guide treatment decisions in HCC.

Clinical applications of circulating tumor DNA in monitoring breast cancer drug resistance

2020 ◽  
Vol 16 (34) ◽  
pp. 2863-2878
Author(s):  
Yang Liu ◽  
Qian Du ◽  
Dan Sun ◽  
Ruiying Han ◽  
Mengmeng Teng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Clinical Applications ◽  
Current Status ◽  
Cancer Drug ◽  
Genomic Alteration ◽  
Tumor Dna

Breast cancer is one of the leading causes of cancer-related deaths in women worldwide. Unfortunately, treatments often fail because of the development of drug resistance, the underlying mechanisms of which remain unclear. Circulating tumor DNA (ctDNA) is free DNA released into the blood by necrosis, apoptosis or direct secretion by tumor cells. In contrast to repeated, highly invasive tumor biopsies, ctDNA reflects all molecular alterations of tumors dynamically and captures both spatial and temporal tumor heterogeneity. Highly sensitive technologies, including personalized digital PCR and deep sequencing, make it possible to monitor response to therapies, predict drug resistance and tailor treatment regimens by identifying the genomic alteration profile of ctDNA, thereby achieving precision medicine. This review focuses on the current status of ctDNA biology, the technologies used to detect ctDNA and the potential clinical applications of identifying drug resistance mechanisms by detecting tumor-specific genomic alterations in breast cancer.

scholarly journals Mechanisms of Acquired Resistance to Savolitinib, a Selective MET Inhibitor in MET-Amplified Gastric Cancer

2020 ◽  
pp. 222-232 ◽  
Author(s):  
Melanie M. Frigault ◽  
Aleksandra Markovets ◽  
Barrett Nuttall ◽  
Kyoung-Mee Kim ◽  
Se Hoon Park ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Progression ◽  
Tumor Tissue ◽  
Treatment Options ◽  
Acquired Resistance ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Met Inhibitor ◽  
Tumor Dna ◽  
Generation Sequencing

PURPOSE Some gastric cancers harbor MET gene amplifications that can be targeted by selective MET inhibitors to achieve tumor responses, but resistance eventually develops. Savolitinib, a selective MET inhibitor, is beneficial for treating patients with MET-driven gastric cancer. Understanding the resistance mechanisms is important for optimizing postfailure treatment options. PATIENTS AND METHODS Here, we identified the mechanisms of acquired resistance to savolitinib in 3 patients with gastric cancer and MET-amplified tumors who showed a clinical response and then cancer progression. Longitudinal circulating tumor DNA (ctDNA) is useful for monitoring resistance during treatment and progression when rebiopsy cannot be performed. RESULTS Using a next-generation sequencing 100-gene panel, we identified the target mechanisms of resistance MET D1228V/N/H and Y1230C mutations or high copy number MET gene amplifications that emerge when resistance to savolitinib develops in patients with MET-amplified gastric cancer. CONCLUSION We demonstrated the utility of ctDNA in gastric cancer and confirmed this approach using baseline tumor tissue or rebiopsy.

scholarly journals Development of circulating tumour DNA analysis for gastrointestinal cancers

ESMO Open ◽  
2020 ◽  
Vol 5 (Suppl 1) ◽  
pp. e000600 ◽  
Author(s):  
Yoshiaki Nakamura ◽  
Kohei Shitara
Keyword(s):  
Dna Analysis ◽  
Residual Disease ◽  
Turnaround Time ◽  
Resistance Mechanisms ◽  
Detection Methods ◽  
Comprehensive Genomic Profiling ◽  
Gi Cancers ◽  
Ctdna Analysis ◽  
Next Generation Sequencing Ngs ◽  
Circulating Tumour Dna

Comprehensive genomic profiling using next-generation sequencing (NGS) enables the identification of multiple genomic biomarkers established in advanced gastrointestinal (GI) cancers. However, tissue-based NGS has limitations, such as long turnaround time and failure to detect tumour heterogeneity. Recently, the analysis of circulating tumour DNA (ctDNA) using polymerase chain reaction-based or NGS-based methods has demonstrated the capability to detect genomic alterations with high accuracy compared with tumour tissue analysis with short turnaround time and identify heterogeneous resistance mechanisms. Furthermore, ctDNA analysis can be repeatedly performed on disease progression to clarify resistant clones. Clinical trials that test the outcome of a selected targeted therapy based on a ctDNA result are ongoing to prospectively evaluate the clinical utility of ctDNA analysis. Furthermore, the improvement of ctDNA analysis beyond current technical limits of mutation-based ctDNA detection methods has expanded the potential for detecting the presence of tumours in patients with no clinically evident disease, such as minimal residual disease and early cancer. Although a careful understanding of the advantages and limitations are required and further prospective studies are needed, the ctDNA analysis has the potential to overcome several challenges in the treatment of various types of cancers at all stages, including GI cancers.

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