EGFR circulating tumour DNA testing: identification of predictors of ctDNA detection and implications for survival outcomes (original) (raw)
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Current cancer drug targets, 2018
Recent studies evaluated the diagnostic accuracy of circulating tumor DNA (ctDNA) in the detection of epidermal growth factor receptor (EGFR) mutations from plasma of NSCLC patients, overall showing a high concordance as compared to standard tissue genotyping. However it is less clear if the location of metastatic site may influence the ability to identify EGFR mutations in plasma. This pooled analysis aims to evaluate the association between the metastatic site location and the sensitivity of ctDNA analysis in detecting EGFR mutations in NSCLC patients. Data from all published studies, evaluating the sensitivity of plasma-based EGFR-mutation testing, stratified by metastatic site location (extrathoracic (M1b) vs intrathoracic (M1a)) were collected by searching in PubMed, Cochrane Library, American Society of Clinical Oncology, and World Conference of Lung Cancer, meeting proceedings. Pooled Odds ratio (OR) and 95% confidence intervals (95% CIs) were calculated for the ctDNA analysi...
Współczesna Onkologia
The main purpose of this study was to assess detection of mutations in the epidermal growth factor receptor (EGFR) gene in circulating tumor DNA (ctDNA) as a tool for EGFR tyrosine kinase inhibitor (TKI) monitoring therapy. Material and methods: The study was conducted using 20 samples from 7 adenocarcinoma patients treated with TKIs. Blood samples for ctDNA analysis were collected in 2015-2016. ctDNA was isolated using the QIAamp Circulating Nucleic Acid Kit (Qiagen) and analyzed using the ctEGFR Mutation Detection Kit (EntroGen). Results: The most common exon 19 deletion and p.Leu858Arg mutation in exon 21 of the EGFR gene were detected. We observed a correlation between stabilization of patient condition and the lack of p.Thr790Met mutation detection in ctEGFR during TKI treatment (2 out of 7 patients). We also observed a correlation between progression of the disease and p.Thr790Met mutation detection in ctEGFR (3 out of 7 cases). We did not detect ctDNA p.Thr790Metp in two patients in whom progression occurred shortly thereafter. Last but not least, we noticed that good organization during plasma collection and transportation (average time of 6 minutes and 30 seconds) allows to use K2EDTA tubes. Conclusions: When tissue is limited or insufficient, analysis of the ctEGFR mutational status can be considered as an alternative tool for qualifying patients with non-small cell lung cancer (NSCLC) for TKI therapy, also as a potential monitoring tool. The plasma p.Thr790Met-negative result needs to be verified for the presence of p.Thr790Met-positive tumor tissue.
Journal of Thoracic Disease, 2019
Background: The non-interventional ASSESS study (NCT01785888) evaluated the utility of circulating free tumor-derived DNA (ctDNA) from plasma for epidermal growth factor receptor (EGFR) mutation testing in patients with advanced non-small-cell lung cancer (NSCLC), in a real-world setting across 56 centers in Europe and Japan. The high mutation status concordance between 1162 matched tissue/cytology and plasma samples (89%, sensitivity =46%, specificity =97%) suggested that ctDNA is a feasible sample for EGFR mutation analysis. We report data for the French subset of patients (pre-planned analysis). Methods: Eligible patients (stage IIIA/B/IV locally advanced/metastatic treatment-naive advanced NSCLC) provided diagnostic tissue/cytology and plasma samples. DNA extracted from tissue/cytology samples was subjected to EGFR mutation testing as per local practice; a designated laboratory performed ctDNA extraction/mutation testing of plasma samples. The primary outcome was EGFR mutation status concordance between matched tumor and plasma samples. Results: Of the 1,311 patients enrolled in the ASSESS trial, 145 were recruited from 9 centers in France. Tumor samples from 130 patients were collected and 126 were evaluable for EGFR mutation analysis. Activating EGFR mutations were identified in 13 of the 126 patient tumor samples (EGFR mutation frequency 10.3%). For plasma testing, 10 of the 145 samples tested were positive for EGFR mutations (EGFR mutation frequency 6.9%). EGFR mutation rate was significantly higher in never-versus ever-smokers (stepwise logistic regression: tumor, P<0.0001; plasma, P=0.0008). Mutation status concordance between 126 matched patient samples was 96.0% [121/126; 95% confidence intervals (CI), 91.0-98.7]. Of the 113 EGFR mutation-negative patient tissue samples, one tested plasma-positive; reanalysis of plasma via two different techniques confirmed the presence of a L858R mutation, indicating a tissue false-negative result. Based on these data, sensitivity of plasma testing was 64.3% (9/14; 95% CI, 35.1-87.2%) and its specificity was 100.0% (112/112; 95% CI, 96.8-100.0%).
Journal of Clinical Pathology
AimsEpidermal growth factor receptor (EGFR) T790M mutations can be detected in the circulating tumour DNA from plasma of patients with non-small cell lung cancer (NSCLC) to triage patients for osimertinib eligibility and monitor patients longitudinally for development of T790M-mediated resistance.MethodsUsing droplet digital PCR (ddPCR), we examined the EGFR T790M status of 343 sequential patients with NSCLC and correlated mutational status with demographic and clinical features. Where available, serial T790M blood test results were assessed to identify clinical triggers and timing of repeat testing.ResultsOf the 343 patients with liquid biopsy test results, 24% were T790M positive. No clear clinical correlation with a T790M positive test result was identified in this study, although the number of metastatic sites did correlate significantly with the presence of EGFR sensitising mutations (L858R or exon 19 deletion) in patient plasma, as a measure of tumour DNA shedding. Of the 59 s...
Translational Lung Cancer Research
Background: Developing liquid biopsy technology with higher sensitivity and specificity especially for low-frequency mutations remains crucial. This study demonstrated superior performance of the newly developed digital PCR (dPCR) kit for ctDNA-based EGFR p.T790M detection in metastatic non-small-cell lung cancer (NSCLC) against ARMS-PCR. Methods: This large-scale, multi-centered diagnostic study recruited 1,045 patients including 1,029 patients diagnosed with advanced NSCLC and 16 patients with specific samples between April 1 st 2018 and November 30 th 2019. EGFR p.T790M in plasma samples from mNSCLC patients were tested using dPCR with ADx-ARMS PCR and Cobas ® EGFR Mutation Test V2 as comparator assays to confirm cutoff value Xu et al. The performance of dPCR in detecting ctDNA-EGFR p.T790M
Scientific Reports
-T790M mutation testing by ctDNA were collected by searching in PubMed, Cochrane Library, American Society of Clinical Oncology, European Society of Medical Oncology and World Conference of Lung Cancer meeting proceedings. A total of twenty-one studies, with 1639 patients, were eligible. The pooled sensitivity of ctDNA analysis was 0.67 (95% CI: 0.64-0.70) and the pooled specificity was 0.80 (95% CI: 0.77-0.83). The pooled positive predictive value (PPV) was 0.85 (95% CI: 0.82-0.87) and the pooled negative predictive value (NPV) was 0.60 (95% CI: 0.56-0.63). The positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 2.67 (95% CI: 1.86-3.82) and 0.46 (95% CI: 0.38-0.54), respectively. The pooled diagnostic odds ratio (DOR) was 7.27 (4.39-12.05) and the area under the curve (AUC) of the summary receiver operating characteristics (sROC) curve was 0.77. The ctDNA analysis represents a promising, non-invasive approach to detect and monitor the T790M mutation status in NSCLC patients. Development of standardized methodologies and clinical validation are recommended.
Prognostic value of quantitative ctDNA levels in non small cell lung cancer patients
Oncotarget, 2018
Circulating tumor DNA (ctDNA) levels correlate well with tumor bulk. In this paper we aim to estimate the prognostic value of the dynamic quantification of ctDNA levels. A total of 251 serial plasma samples from 41 non-small-cell lung cancer patients who carried an activating EGFR mutation were analysed by digital PCR. For survival analysis, ctDNA levels were computed as a time-dependent covariate. Dynamic ctDNA measurements had prognostic significance (hazard ratio for overall survival and progression free survival according to p.T790M mutant allele frequency; 2.676 and 2.71 respectively;< 0.05). In the same way, patients with p.T790M-negative or unchanging or decreasing plasma levels of sensitizing EGFR mutation were 12 and 4.8 times more likely to maintain response or stable disease, respectively, than patients in which the opposite occurred (< 0.05).On average, the p.T790M mutation was detected in plasma 51 days before the assessment of progression disease by CT-scan. Fina...
Association of EGFR L858R Mutation in Circulating Free DNA With Survival in the EURTAC Trial
JAMA Oncology, 2015
The EURTAC trial demonstrated the greater efficacy of erlotinib compared with chemotherapy for the first-line treatment of European patients with advanced non-small-cell lung cancer (NSCLC) harboring oncogenic epidermal growth factor receptor (EGFR) mutations (exon 19 deletion or L858R mutation in exon 21) in tumor tissue. OBJECTIVE To assess the feasibility of using circulating free DNA (cfDNA) from blood samples as a surrogate for tumor biopsy for determining EGFR mutation status and to correlate EGFR mutations in cfDNA with outcome.