Monitoring of the presence of EGFR-mutated DNA during EGFR-targeted therapy may assist in the prediction of treatment outcome

Moiseenko, Fedor; Volkov, Nikita; Жабина, А. С.; Stepanova, M.; Rysev, N.; Клименко, В. В.; Myslik, A.; Artemieva, E. V.; Egorenkov, V.V.; Abduloeva, N H; Ivantsov, Alexandr O.; Kuligina, Ekatherina Sh.; Imyanitov, Evgeny N.; Moiseyenko, Vladimir

doi:10.1016/j.ctarc.2022.100524

Cited by 7 publications

(14 citation statements)

References 41 publications

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“…Our results show that ctDNA baseline load as well as dynamics can be prognostic, and that ctDNA clearance at C3 portends better outcomes. This is consistent with results in previous studies, which also show that molecular progression can predate and predict clinical progression [33][34][35]. The role that sequential assessment of ctDNA should play moving forward remains to be seen.…”

Section: Discussionsupporting

confidence: 91%

A Phase II Study of Osimertinib in Patients with Advanced-Stage Non-Small Cell Lung Cancer following Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) Therapy with EGFR and T790M Mutations Detected in Plasma Circulating Tumour DNA (PLASMA Study)

Ang,

Zhao,

Reungwetwattana

et al. 2023

Cancers

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Epidermal growth factor receptor (EGFR) T790M mutations drive resistance in 50% of patients with advanced non-small cell lung cancer (NSCLC) who progress on first/second generation (1G/2G) EGFR tyrosine kinase inhibitors (TKIs) and are sensitive to Osimertinib. Tissue sampling is the gold-standard modality of T790M testing, but it is invasive. We evaluated the efficacy of Osimertinib in patients with EGFR mutant NSCLC and T790M in circulating tumour DNA (ctDNA). PLASMA is a prospective, open-label, multicentre single-arm Phase II study. Patients with advanced NSCLC harbouring sensitizing EGFR and T790M mutations in plasma at progression from ≥one 1G/2G TKI were treated with 80 mg of Osimertinib daily until progression. The primary endpoint was the objective response rate (ORR); the secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and toxicities. Plasma next-generation sequencing was performed to determine Osimertinib resistance mechanisms and assess serial ctDNA. A total of 110 patients from eight centres in five countries were enrolled from 2017 to 2019. The median follow-up duration was 2.64 (IQR 2.44–3.12) years. The ORR was 50.9% (95% CI 41.2–60.6) and the DCR was 84.5% (95% CI 76.4–90.7). Median PFS was 7.4 (95% CI 6.0–9.3) months; median OS was 1.63 (95% CI 1.35–2.16) years. Of all of the patients, 76% had treatment-related adverse events (TRAEs), most commonly paronychia (22.7%); 11% experienced ≥ Grade 3 TRAEs. The ctDNA baseline load and dynamics were prognostic. Osimertinib is active in NSCLC harbouring sensitizing EGFR and T790M mutations in ctDNA testing post 1G/2G TKIs.

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Section: Discussionsupporting

confidence: 91%

A Phase II Study of Osimertinib in Patients with Advanced-Stage Non-Small Cell Lung Cancer following Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) Therapy with EGFR and T790M Mutations Detected in Plasma Circulating Tumour DNA (PLASMA Study)

Ang,

Zhao,

Reungwetwattana

et al. 2023

Cancers

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“…Two meta-analyses demonstrated a pooled specificity of 93.5–98% and a sensitivity of 67.4–68% for cfDNA, when plasma samples were tested to determine the EGFR mutational status compared with matched tumor tissues [ 23 , 25 ]. The cobas ® EGFR Mutation Test v2 is easy to operate and stable for the screening of plasma EGFR mutations in routine clinical settings [ 3 , 26 ], compared with the limitations associated with NGS in liquid biopsy, such as limited equipment availability, cumbersome assay, and a long turnaround time [ 27 ]. However, RT-PCR or emulsion PCR techniques, such as digital Bead Emulsion Amplification and Magnetic (BEAMing) and ddPCR, are not suitable for analyzing the complex and multiple genomic aberrations emerging as relevant targets for precision medicine in NSCLC [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Analytical Performance of Oncomine Lung cfDNA Assay for Detection of Plasma EGFR Mutations

Cho

Park

Han

et al. 2023

Genes

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Background: The clinical utility of circulating tumor DNA (ctDNA) in the early detection of tumor mutations for targeted therapy and the monitoring of tumor recurrence has been reported. However, the analytical validation of ctDNA assays is required for clinical application. Methods: This study evaluated the analytical performance of the Oncomine Lung cfDNA Assay compared with the cobas® EGFR Mutation Test v2. The analytical specificity and sensitivity were estimated using commercially pre-certified reference materials. The comparative evaluation of the two assays was carried out using reference materials and plasma derived from patients diagnosed with lung cancer. Results: Using 20 ng of input cell-free DNA (cfDNA), the analytical sensitivities for EGFR mutations with variant allele frequencies (VAFs) of 1% and 0.1% were 100% and 100%, respectively. With VAFs of 1.2% and 0.1% using 20 ng of input cfDNA, seven out of nine different mutations in six driver genes were identified in the Oncomine Lung cfDNA Assay. The two assays showed 100% concordance in 16 plasma samples clinically. Furthermore, various PIK3CA and/or TP53 mutations were identified only in the Oncomine Lung cfDNA Assay. Conclusions: The Oncomine Lung cfDNA Assay can be used to identify plasma EGFR mutations in patients with lung cancer, although further large-scale studies are required to evaluate the analytical validity for other types of aberrations and genes using clinical samples.

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“…Of these, 14 cohorts from 11 studies that reported on 1359 patients described the association of baseline ctDNA levels and clinical outcomes and were grouped into Category A (Cat A) studies [28][29][30][31][32][33][34][35][36]. The other 18 cohorts from 16 studies that reported on 1659 patients that described the association of dynamic changes in ctDNA with clinical outcomes were grouped as Category B (Cat B) studies [29,32,34,[36][37][38][39][40][41][42][43][44][45][46][47][48]. To note, six studies [29,32,[34][35][36]44] qualified for both categories and hence were included in both categories, respectively.…”

Section: Characteristics Of Included Studiesmentioning

confidence: 99%

“…The other 18 cohorts from 16 studies that reported on 1659 patients that described the association of dynamic changes in ctDNA with clinical outcomes were grouped as Category B (Cat B) studies [29,32,34,[36][37][38][39][40][41][42][43][44][45][46][47][48]. To note, six studies [29,32,[34][35][36]44] qualified for both categories and hence were included in both categories, respectively. Data from all 27 studies analysed PFS, 19 cohorts considered OS (5 in Cat A [29,32,35,36,44] and 14 in Cat B [29,[34][35][36][38][39][40][42][43][44][45]48].…”

Section: Characteristics Of Included Studiesmentioning

confidence: 99%

Circulating Tumour DNA (ctDNA) as a Predictor of Clinical Outcome in Non-Small Cell Lung Cancer Undergoing Targeted Therapies: A Systematic Review and Meta-Analysis

Zaman

Subramaniam

Afroz

et al. 2023

Cancers

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Background: Liquid biopsy (LB) analysis using (ctDNA)/cell-free DNA (cfDNA) is an emerging alternative to tissue profiling in (NSCLC). LB is used to guide treatment decisions, detect resistance mechanisms, and predicts responses, and, therefore, outcomes. This systematic review and meta-analysis evaluated the impact of LB quantification on clinical outcomes in molecularly altered advanced NSCLC undergoing targeted therapies. Methods: We searched Embase, MEDLINE, PubMed, and Cochrane Database, between 1 January 2020 and 31 August 2022. The primary outcome was progression-free survival (PFS). Secondary outcomes included overall survival (OS), objective response rate (ORR), sensitivity, and specificity. Age stratification was performed based on the mean age of the individual study population. The quality of studies was assessed using the Newcastle–Ottawa Scale (NOS). Results: A total of 27 studies (3419 patients) were included in the analysis. Association of baseline ctDNA with PFS was reported in 11 studies (1359 patients), while that of dynamic changes with PFS was reported in 16 studies (1659 patients). Baseline ctDNA-negative patients had a trend towards improved PFS (pooled hazard ratio [pHR] = 1.35; 95%CI: 0.83–1.87; p < 0.001; I2 = 96%) than ctDNA-positive patients. Early reduction/clearance of ctDNA levels after treatment was related to improved PFS (pHR = 2.71; 95%CI: 1.85–3.65; I2 = 89.4%) compared to those with no reduction/persistence in ctDNA levels. The sensitivity analysis based on study quality (NOS) demonstrated improved PFS only for good [pHR = 1.95; 95%CI: 1.52–2.38] and fair [pHR = 1.99; 95%CI: 1.09–2.89] quality studies, but not for poor quality studies. There was, however, a high level of heterogeneity (I2 = 89.4%) along with significant publication bias in our analysis. Conclusions: This large systematic review, despite heterogeneity, found that baseline negative ctDNA levels and early reduction in ctDNA following treatment could be strong prognostic markers for PFS and OS in patients undergoing targeted therapies for advanced NSCLC. Future randomised clinical trials should incorporate serial ctDNA monitoring to further establish the clinical utility in advanced NSCLC management.

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Monitoring of the presence of EGFR-mutated DNA during EGFR-targeted therapy may assist in the prediction of treatment outcome

Cited by 7 publications

References 41 publications

A Phase II Study of Osimertinib in Patients with Advanced-Stage Non-Small Cell Lung Cancer following Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) Therapy with EGFR and T790M Mutations Detected in Plasma Circulating Tumour DNA (PLASMA Study)

A Phase II Study of Osimertinib in Patients with Advanced-Stage Non-Small Cell Lung Cancer following Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) Therapy with EGFR and T790M Mutations Detected in Plasma Circulating Tumour DNA (PLASMA Study)

Evaluation of the Analytical Performance of Oncomine Lung cfDNA Assay for Detection of Plasma EGFR Mutations

Circulating Tumour DNA (ctDNA) as a Predictor of Clinical Outcome in Non-Small Cell Lung Cancer Undergoing Targeted Therapies: A Systematic Review and Meta-Analysis

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