Dataset Information

Plasma EGFR T790M ctDNA status is associated with clinical outcome in advanced NSCLC patients with acquired EGFR-TKI resistance.

ABSTRACT: EGFR T790M mutation occurs in half of non-small cell lung cancer (NSCLC) patients with acquired EGFR-TKI (TKI) resistance, based on tumor re-biopsies using an invasive clinical procedure. Here, we dynamically monitored T790M mutation in circulating tumor DNA (ctDNA) using serial plasma samples from NSCLC patients receiving TKI through Droplet Digital PCR (ddPCR) method and the associations between overall survival (OS) starting from initial TKI treatment and the T790M ctDNA status detected in plasma were analyzed. Among 318 patients, 117 who acquired TKI resistance were eligible for the analysis. T790M ctDNA was detected in the plasma of 55/117 (47%) patients. Almost half of the T790M ctDNA positive patients were identified at a median time of 2.2 months prior to clinically progressive disease (PD). Furthermore, within the patients receiving TKI treatment at 2(nd) line or later, the T790M ctDNA positive group had significantly shorter OS than the negative group (median OS: 26.9 months versus NA, P?=?0.0489). Our study demonstrates the feasibility of monitoring EGFR mutation dynamics in serial plasma samples from NSCLC patients receiving TKI therapy. T790M ctDNA can be detected in plasma before and after PD as a poor prognostic factor.

SUBMITTER: Zheng D

PROVIDER: S-EPMC4751431 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Plasma EGFR T790M ctDNA status is associated with clinical outcome in advanced NSCLC patients with acquired EGFR-TKI resistance.

Zheng D D Ye X X Zhang M Z MZ Sun Y Y Wang J Y JY Ni J J Zhang H P HP Zhang L L Luo J J Zhang J J Tang L L Su B B Chen G G Zhu G G Gu Y Y Xu J F JF

Scientific reports 20160212

EGFR T790M mutation occurs in half of non-small cell lung cancer (NSCLC) patients with acquired EGFR-TKI (TKI) resistance, based on tumor re-biopsies using an invasive clinical procedure. Here, we dynamically monitored T790M mutation in circulating tumor DNA (ctDNA) using serial plasma samples from NSCLC patients receiving TKI through Droplet Digital PCR (ddPCR) method and the associations between overall survival (OS) starting from initial TKI treatment and the T790M ctDNA status detected in pl ...[more]

PMID: 26867973

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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.

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:BackgroundHER2 (or ERBB2) amplification is an important mechanism for acquired resistance to EGFR tyrosine kinase inhibitors (TKI). The benefits of HER2-targeted therapy have been limited. Herein, we investigated the molecular and clinical patterns of HER2 amplification in non-small cell lung cancer (NSCLC) patients during progression on EGFR-TKIs and the potential of combining EGFR-TKI and pyrotinib to overcome resistance.MethodsIn this study, 1,637 NSCLC cases from Geneseeq after progression of EGFR-TKIs were screened and analyzed by next generation sequencing (NGS), in which 48 patients with HER2 amplification were eligible and enrolled. A total of 403 patients from Sun Yat-sen University Cancer Center (SYSUCC) were screened and five patients with concomitant EGFR mutations and HER2 amplification were retrospectively collected to assess the effect of afatinib or combination of EGFR-TKI and pyrotinib.ResultsIn the 48 patients from the Geneseeq cohort, 27 (56.2%) patients suffered from resistance of 1st/2nd generation EGFR-TKI, and 21 (43.8%) patients from 3rd generation. As for the five patients forming the SYSUCC cohort, three patients were treated with afatinib, one achieved partial response (PR) with progression-free survival (PFS) of 6 months and two quickly developed disease progression. Two patients were treated with EGFR-TKIs plus pyrotinib, one receiving gefitinib plus pyrotinib achieved PR with PFS of 8 months and benefited from osimertinib plus pyrotinib for 3 months till data-off; one receiving osimertinib plus pyrotinib achieved SD for 4 months till data-off. The most common co-occurring alteration was TP53 (91.7%) in the mutation profile of the 48 patients from the Geneseeq cohort, and four patients had TP53 co-mutations of the five patients from the SYSUCC cohort.ConclusionIn this study, we detected 7% HER2 amplification present in EGFR-TKIs resistance. Patients with concomitant EGFR mutation and HER2 amplification may derive clinical benefit from therapies that target both EGFR and HER2.

Project description:In Taiwan, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs), gefitinib, erlotinib, and afatinib are served as first-line therapy for non-small lung cell cancer (NSCLC) patients with EGFR sensitizing mutations. However, the majority of patients who initially respond to EGFR-TKIs, progress through acquiring EGFR T790M mutations (T790M), which is the most common resistant mechanism. Patients with T790M gain the opportunity of subsequent treatment with third-generation EGFR-TKI, osimertinib. This study aimed to evaluate the association between prior EGFR-TKI therapy and incidence of acquired T790M resistance in lung adenocarcinoma patients who have progressed on first/second-generation EGFR-TKI therapy. This retrospective study included lung adenocarcinoma patients who had a radiographically-confirmed progressive disease under EGFR-TKI treatment and had re-biopsy samples for T790M testing from seven medical centers in Taiwan from June 2013 to December 2018. Patients harboring de novo T790M or using more than one EGFR-TKI were excluded. Of the 407 patients enrolled, the overall T790M acquisition rate was 52.8%. The patients treated with gefitinib, erlotinib or afatinib had a statistically significant difference in the T790M rates (59.9, 45.5, and 52.7%, respectively; p = 0.037) after disease progression. Patients with common baseline EGFR mutations (Del-19 and L858R) (p = 0.005) and longer treatment duration with EGFR-TKIs (p < 0.001) had higher chances of T790M acquisition. Multivariate logistic regression analysis further showed that patients with common baseline EGFR mutations, gefitinib (compared to erlotinib) administration, and longer treatment duration with EGFR-TKIs had higher T790M incidence. There was no significant difference in the incidence of acquired T790M between different re-biopsy tissue samples or complications. In conclusion, this study showed that patients who progressed from gefitinib treatment, bearing common EGFR mutations, and with longer EGFR-TKI treatment duration had increased incidence of T790M acquisition and, therefore, were suitable for subsequent osimertinib treatment.

Dataset Information

Plasma EGFR T790M ctDNA status is associated with clinical outcome in advanced NSCLC patients with acquired EGFR-TKI resistance.

Publications

Plasma EGFR T790M ctDNA status is associated with clinical outcome in advanced NSCLC patients with acquired EGFR-TKI resistance.

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