Dynamics of EGFR mutations in plasma recapitulates the clinical response to EGFR-TKIs in NSCLC patients

Xiong, Liwen; Cui, Sen; Ding, Jianyong; Sun, Yun-Fan; Zhang, Longfu; Zhao, Yupei; Gu, Aiqin; Chu, Tianqing; Wang, Huimin; Ye, Xin; Gu, Yi; Zhang, Xin; Hu, Min; Jiang, Liyan

doi:10.18632/oncotarget.19139

Cited by 21 publications

(22 citation statements)

References 40 publications

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“…Though all plasma ctDNA T790M decreased to very low level, no association was observed with radiographic response. Previous studies dynamically monitored EGFR mutation status using plasma samples by ddPCR to evaluate response to first generation EGFR TKIs [ 16 ]. Another study quantified plasma T790M level in two cases of patients who received osimertinib treatment [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

EGFR T790M detection and osimertinib treatment response evaluation by liquid biopsy in lung adenocarcinoma patients with acquired resistance to first generation EGFR tyrosine kinase inhibitors

Jia

Liu

et al. 2018

Diagn Pathol

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BackgroundLung adenocarcinoma with EGFR activating mutations will inevitably acquire resistance to first generation TKIs. Acquired EGFR T790M mutation causes about 50% of these resistance cases. Droplet digital PCR (ddPCR) and cobas enables quantification of T790M mutation. Whether these methods can predict clinical response of osimertinib treatment is unknown.MethodsTumor and blood samples from 69 stage IIIB-IV NSCLC patients acquired resistance to EGFR-TKI were collected. Cobas® Mutation Test v2 kit was used to detect EGFR mutations in FFPE or plasma samples. Plasma T790M mutation of both osimertinib naïve and treated patients were quantified by Droplet digital PCR (ddPCR).ResultsT790M mutation rate detected by FFPE tissue cobas, plasma ctDNA cobas and plasma ctDNA ddPCR test were 54.5, 21.3 and 30.4% respectively. The T790M positive rate was 52.2% considering all testing methods. The objective response rate (ORR) was 60.9% in 23 patients received osimertinib treatment. Quantification of T790M after treatment decreased to very low level, but no association was observed between clinical response and T790M mutation level decrease.ConclusionddPCR is more sensitive in plama ctDNA testing and should be performed even in tumor tissue T790M test negative cases. EGFR T790M mutation level is not associated with clinical response after osimertinib treatment.

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Section: Discussionmentioning

confidence: 99%

EGFR T790M detection and osimertinib treatment response evaluation by liquid biopsy in lung adenocarcinoma patients with acquired resistance to first generation EGFR tyrosine kinase inhibitors

Jia

Liu

et al. 2018

Diagn Pathol

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“…Furthermore, if ctDNA is present after curative treatment, the risk of relapse is significantly increased (Garcia‐Murillas et al , ). Likewise, an increase in the concentration of ctDNA during ongoing treatment precedes disease progression (Demuth et al , ; Provencio et al , ; Xiong et al , ). These findings offer new hope for monitoring disease activity using ctDNA and emphasise how ctDNA may be a valuable tool in the treatment–decision pathway in the near future.…”

Section: Introductionmentioning

confidence: 99%

Intra‐individual variation of circulating tumour DNA in lung cancer patients

et al. 2019

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Circulating tumour DNA (ctDNA) has been increasingly incorporated into the treatment of cancer patients. ctDNA is generally accepted as a powerful diagnostic tool, whereas the utility of ctDNA to monitor disease activity needs to be fully validated. Central to this challenge is the question of whether changes in longitudinal ctDNA measurements reflect disease activity or merely biological variation. Thus, the aim of this study was to explore the intra‐individual biological variation of ctDNA in lung cancer patients. We identified tumour‐specific mutations using next‐generation sequencing. Day‐to‐day and hour‐to‐hour variations in plasma concentrations of the mutant allele and wild‐type cell‐free DNA (cfDNA) were determined using digital PCR. The levels of the mutant alleles varied by as much as 53% from day to day and 27% from hour to hour. cfDNA varied up to 19% from day to day and up to 56% from hour to hour, as determined using digital PCR. Variations were independent of the concentration. Both mutant allele concentrations and wild‐type cfDNA concentrations showed considerable intra‐individual variation in lung cancer patients with nonprogressive disease. This pronounced biological variation of the circulating DNA should be investigated further to determine whether ctDNA can be used for monitoring cancer activity.

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“…Thus, studies have focused on detecting and monitoring alterations in epidermal growth factor receptor ( EGFR ) and rearrangements of the anaplastic lymphoma kinase ( ALK ) during treatment with targeted therapies [ 7 , 15 – 17 ]. By monitoring the abundance of EGFR mutations using ctDNA, studies have found correlation between decreasing ctDNA levels and tumour response on conventional imaging [ 18 – 20 ]. Further, whether or not EGFR mutations in ctDNA are cleared to an undetectable level may be predictive of response to EGFR-TKI therapy [ 21 – 23 ].…”

Section: Introductionmentioning

confidence: 99%

A method for treatment monitoring using circulating tumour DNA in cancer patients without targetable mutations

et al. 2018

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BackgroundThe potentials of circulating tumour DNA (ctDNA) have been studied for non-invasive disease monitoring in patients with targetable mutations. However, the majority of cancer patients harbour no targetable mutations. A workflow including targeted next-generation sequencing (NGS) and droplet digital PCR (ddPCR) could be used for monitoring treatment in these patients. Thus, our aim was to evaluate the workflow for ctDNA monitoring in a cohort of non-small cell lung cancer patients.MethodsForty patients were prospectively included. Plasma samples were collected prior to and during treatment. NGS (Ion AmpliSeq Colon and Lung Cancer panel v2) was performed on ctDNA from pre-treatment samples. The identified mutations were monitored by ddPCR in consecutively collected samples.ResultsMutations were detected in 21 patients. The most commonly mutated genes were TP53 (N=20) and KRAS (N=13). Treatment was discontinued due to non-response in 18 patients. In 16 of these, a simultaneous increase in ctDNA concentration was observed. A twofold ctDNA concentration increase confirmed in a second successive sample predicted non-response on the following imaging in 83% of patients (10/12).ConclusionctDNA monitoring can be used for early detection of non-response in patients without targetable mutations, and therefore could supplement imaging data for treatment monitoring in this subset of patients.

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Dynamics of EGFR mutations in plasma recapitulates the clinical response to EGFR-TKIs in NSCLC patients

Cited by 21 publications

References 40 publications

EGFR T790M detection and osimertinib treatment response evaluation by liquid biopsy in lung adenocarcinoma patients with acquired resistance to first generation EGFR tyrosine kinase inhibitors

EGFR T790M detection and osimertinib treatment response evaluation by liquid biopsy in lung adenocarcinoma patients with acquired resistance to first generation EGFR tyrosine kinase inhibitors

Intra‐individual variation of circulating tumour DNA in lung cancer patients

A method for treatment monitoring using circulating tumour DNA in cancer patients without targetable mutations

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