Dataset Information

Compared to plasma, bronchial washing fluid shows higher diagnostic yields for detecting EGFR-TKI sensitizing mutations by ddPCR in lung cancer.

ABSTRACT: BACKGROUND:The rate of diagnosis of advanced lung adenocarcinoma must be improved. In this study, we compared the detection rates of EGFR-tyrosine kinase inhibitor-sensitizing mutations (mEGFRs) in bronchial washing fluid (BWF) and the plasma of patients with lung adenocarcinoma using the tissue genotype as the standard reference. METHODS:Paired blood and BWF specimens were collected from 73 patients with lung cancer. The tumor EGFR mutation status was determined by genotyping of the plasma and BWF samples using droplet digital PCR (ddPCR). RESULTS:The study cohort included 26, 10, 10, and 27 patients with stage I, II, III, and IV disease. Of the 73 cases, 35 had a wild-type EGFR, and 19 had the L858R substitution and exon 19 deletion mutations. The areas under the receiver operator characteristic curves for sensitivity vs. specificity of ddPCR were 0.895 [95% confidence interval (CI): 0.822-0.969] for BWF and 0.686 (95% CI: 0.592-0.780) for plasma (p?

SUBMITTER: Lee SH

PROVIDER: S-EPMC7281949 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Compared to plasma, bronchial washing fluid shows higher diagnostic yields for detecting EGFR-TKI sensitizing mutations by ddPCR in lung cancer.

Lee Sang Hoon SH Kim Eun Young EY Kim Taehee T Chang Yoon Soo YS

Respiratory research 20200609 1

<h4>Background</h4>The rate of diagnosis of advanced lung adenocarcinoma must be improved. In this study, we compared the detection rates of EGFR-tyrosine kinase inhibitor-sensitizing mutations (mEGFRs) in bronchial washing fluid (BWF) and the plasma of patients with lung adenocarcinoma using the tissue genotype as the standard reference.<h4>Methods</h4>Paired blood and BWF specimens were collected from 73 patients with lung cancer. The tumor EGFR mutation status was determined by genotyping of ...[more]

PMID: 32517757

Similar Datasets

Project description:Bronchoscopy is a frequently used initial diagnostic procedure for patients with suspected lung cancer (LC). Cytological examinations of bronchial washing (BW) samples obtained during bronchoscopy often yield inconclusive results regarding LC diagnosis. The present study aimed to identify molecular biomarkers as a non-invasive method for LC diagnosis. Aberrant DNA methylation is used as a useful biomarker for LC. Therefore, microarray-based methylation profiling analyses on 13 patient-matched tumor tissues at stages I-III vs. non-tumor tissues were performed, and a group of highly differentially methylated genes was identified. A subsequent analysis using bisulfite-pyrosequencing with additional tissues and cell lines revealed six methylated genes [ADAM metallopeptidase with thrombospondin type 1 motif 20, forkhead box C2 (mesenchyme forkhead 1), NK2 transcription factor related, locus 5 (Drosophila), oligodendrocyte transcription factor 3, protocadherin γ subfamily A 12 (PCDHGA12) and paired related homeobox 1 (PRRX1)] associated with LC. Next, a highly sensitive and accurate detection method, linear target enrichment-quantitative methylation-specific PCR in a single closed tube, was applied for clinical validation using BW samples from patients with LC (n=68) and individuals with benign diseases (n=33). PCDHGA12 and PRRX1 methylation were identified as the best-performing biomarkers to detect LC. The two-marker combination showed a sensitivity of 82.4% and a specificity of 87.9%, with an area under the curve of 0.891. Notably, the sensitivity for small cell LC was 100%. The two-marker combination had a positive predictive value of 93.3% and a negative predictive value of 70.7%. The sensitivity was higher than that of cytology, which only had a sensitivity of 50%. The methylation status of the two-marker combination showed no association with sex, age or stage, but was associated with tumor location and histology. In conclusion, the present study showed that the regulatory regions of PCDHGA12 and PRRX1 are highly methylated in LC and can be used to detect LC in BW specimens as a diagnostic adjunct to cytology in clinical practice.

Project description:BackgroundClinical detection of EGFR-TKI resistance mechanism through tissue can be really challenging due to risks associated with the procedure. Thus, liquid biopsy, especially circulation tumor DNA (ctDNA) analysis, can be an adequate source for biomarker testing in targeted therapy. Our study was aimed at clinical validation of liquid biopsy next-generation sequencing (NGS) by comparison with tissue biopsy, and we also investigated clinical utility of ctDNA NGS on the prediction of TKI outcomes.MethodsUsing hybrid capture panel NGS, we compared the concordance, sensitivity, and specificity of ctDNA using 39 paired plasma and tissue biopsy, and investigated the association between ctDNA genomic alterations of 147 first-generation TKI-relapsed patients and their response to first- and third-generation TKIs.ResultsThe concordance for ctDNA and tissue biopsy was 84.62% among all patients, and even higher among late stage patients (88.24%). Among 147 EGFR-TKI-relapsed patients, T790M was the most common reason for resistance (40.13%). Compared with T790M-positive patients, patients only detected with sensitizing mutations (sensi-mutations) had lower mutant allele frequency (MAF) of sensi-mutations (P = 0.031). TP53 mutation showed negative impact on TKI treatments. In survival analysis of third-generation TKI, we found a positive correlation between ratio of T790M sensi-mutation and PFS (P = 0.018); also, higher MAFs of both sensi-mutation and T790M were observed in the PR group than the SD + PD group.ConclusionsBoth ratio of T790M sensi-mutations and MAFs of EGFR mutations were associated with third-generation TKI outcomes. Thus, incorporation of high-throughput NGS into clinical trials may be crucial to identifying the response to osimertinib, as it provides more comprehensive genomic information.Key pointsHigh concordance of ctDNA and tissue biopsy was observed. NGS of ctDNA from 147 TKI-relapsed patients showed that both high ratio of T790M sensitizing mutation (sensi-mutation) and high MAFs of mutations were all associated with better third generation TKI treatment outcomes. The quantification of both MAFs and T790M sensi-mutation ratio should be taken into consideration in some clinical situations, and incorporation of high-throughput NGS into clinical trials may be crucial to identifying the response to osimertinib, as it provides more comprehensive genomic information.

Project description:There is a discrepancy in the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment for advanced lung adenocarcinoma (LUAD) patients with EGFR sensitizing mutations (mEGFR). Molecular markers other than mEGFR remain to be investigated to better predict EGFR-TKI efficacy. Here, 49 LUAD patients with mEGFR (19 deletions or 21 L858R mutations) who received the first-generation EGFR-TKI icotinib therapy were included and stratified into 25 good-responders with a progression-free survival (PFS) longer than 11 months and 24 poor-responders with a PFS shorter than 11 months. We conducted targeted metabolomic detection and next-generation sequencing on serum and tissue samples, respectively. Subsequently, two metabolomic profiling-based discriminant models were constructed for icotinib efficacy prediction, 10 metabolites overlapped in both models ensured high credibility for distinguishing good- and poor-responders. Seven of the 10 metabolites displayed significant differences between the two groups, which belong to lipids including ceramides (Cers), lysophosphatidylcholines (LPCs), lysophosphatidylethanolamines (LPEs), sphingomyelins (SMs), and free fatty acids (FAs). Briefly, LPC 16:1, LPC 22:5-1, and LPE 18:2 decreased in poor-responders, while Cer 36:1-3, Cer 38:1-3, SM 36:1-2 and SM 42:2 increased in poor-responders. In parallel, we identified 6 co-mutated genes (ARID1A, ARID1B, BCR, FANCD2, PTCH1, and RBM10) which were significantly correlated with a shorter PFS. Additionally, 4 efficacy-related metabolites (Cer 36:1-3, Cer 38:1-3, SM 36:1-2, and LPC 16:1) showed significant differences between the mutant and wild-type of 4 efficacy-related genes (ARID1A, ARID1B, BCR, and RBM10). SM 36:1-2 elevated while LPC 16:1 decreased in ARID1A, BCR, and RBM10 mutant groups compared to the wild-type groups. Cer 36:1-3 increased in the ARID1A and BCR mutant groups, and Cer 38:1-3 only rose in the ARID1A mutant group. Furthermore, we observed a causal-mediator-network-based interrelation between the 4 concurrently mutated genes and the 4 metabolites related metabolic genes in glycerophospholipid metabolism and sphingolipid metabolism pathways. This study demonstrated that lipids metabolism and concurrently mutated genes with mEGFR were associated with the icotinib efficacy, which provides novel perspectives in classifying clinical responses of mEGFR LUAD patients and reveals the potential of non-invasive pretreatment serum metabolites in predicting EGFR-TKI efficacy.

Project description:PurposeWe aimed to evaluate whether the addition of pemetrexed is effective in improving progression-free survival (PFS) in epidermal growth factor receptor (EGFR)-mutated patients with or without concomitant alterations.Materials and methodsThis multicenter clinical trial was conducted in China from June 15, 2018, to May 31, 2019. A total of 92 non-small cell lung cancer (NSCLC) patients harboring EGFR-sensitive mutations were included and divided into concomitant and non-concomitant groups. Patients in each group were randomly treated with EGFR-tyrosine kinase inhibitor (TKI) monotherapy or EGFR-TKI combined with pemetrexed in a ratio of 1:1. PFS was recorded as the primary endpoint.ResultsThe overall median PFS of this cohort was 10.1 months. There were no significant differences in PFS between patients with and without concomitant and between patients received TKI monotherapy and TKI combined with pemetrexed (p=0.210 and p=0.085, respectively). Stratification analysis indicated that patients received TKI monotherapy had a significantly longer PFS in non-concomitant group than that in concomitant group (p=0.002). In concomitant group, patients received TKI combined with pemetrexed had a significantly longer PFS than patients received TKI monotherapy (p=0.013). Molecular dynamic analysis showed rapidly emerging EGFR T790M in patients received TKI monotherapy. EGFR mutation abundance decreased in patients received TKI combined chemotherapy, which supports better efficacy for a TKI combined chemotherapy as compared to TKI monotherapy. A good correlation between therapeutic efficacy and a change in circulating tumor DNA (ctDNA) status was found in 66% of patients, supporting the guiding role of ctDNA minimal residual disease (MRD) in NSCLC treatment.ConclusionEGFR-TKI monotherapy is applicable to EGFR-sensitive patients without concomitant alterations, while a TKI combined chemotherapy is applicable to EGFR-sensitive patients with concomitant alterations. CtDNA MRD may be a potential biomarker for predicting therapeutic efficacy.

Dataset Information

Compared to plasma, bronchial washing fluid shows higher diagnostic yields for detecting EGFR-TKI sensitizing mutations by ddPCR in lung cancer.

Publications

Compared to plasma, bronchial washing fluid shows higher diagnostic yields for detecting EGFR-TKI sensitizing mutations by ddPCR in lung cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets