Dataset Information

The emergence of T790M mutation in EGFR-mutant lung adenocarcinoma patients having a history of acquired resistance to EGFR-TKI: focus on rebiopsy timing and long-term existence of T790M.

ABSTRACT: Different growth kinetics occurring between the sensitive and T790M-containing cells may result in the repopulation of tumor cells over time. Little information has yet been uncovered on whether rebiopsy timing influences the T790M detection rate. We enrolled a total of 98 epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma patients, who had a history of acquired resistance to EGFR-tyrosine kinase inhibitor (TKI) and available rebiopsy tumor specimens for reassessment of EGFR mutations. Rebiopsy was performed at the time of first EGFR-TKI progression in 54 patients (55.1%); for the other 44 patients (44.9%), rebiopsy was done with an interval from first EGFR-TKI progression (median 470.5 days, range 46-1742 days). Our results indicated that rebiopsy timing did not influence the detection rate of T790M and that the mutation could be identified in patients with a long EGFR-TKI-free interval. For patients without suitable lesions for rebiopsy at the time of EGFR-TKI progression, an attempt to rebiopsy should be considered during the subsequent treatment courses.

SUBMITTER: Tseng JS

PROVIDER: S-EPMC5217000 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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The emergence of T790M mutation in EGFR-mutant lung adenocarcinoma patients having a history of acquired resistance to EGFR-TKI: focus on rebiopsy timing and long-term existence of T790M.

Tseng Jeng-Sen JS Su Kang-Yi KY Yang Tsung-Ying TY Chen Kun-Chieh KC Hsu Kuo-Hsuan KH Chen Hsuan-Yu HY Tsai Chi-Ren CR Yu Sung-Liang SL Chang Gee-Chen GC

Oncotarget 20160701 30

Different growth kinetics occurring between the sensitive and T790M-containing cells may result in the repopulation of tumor cells over time. Little information has yet been uncovered on whether rebiopsy timing influences the T790M detection rate. We enrolled a total of 98 epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma patients, who had a history of acquired resistance to EGFR-tyrosine kinase inhibitor (TKI) and available rebiopsy tumor specimens for reassessment of EGFR muta ...[more]

PMID: 27384480

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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.

Project description:Simple Summary Treatment outcomes for non-small cell lung cancer (NSCLC) patients have significantly improved since the introduction of targeted therapy using tyrosine kinase inhibitors (TKI). Despite the initial promising results, most patients develop resistance due to on- or off-target mechanisms. On-target mutations prevent the effective binding of TKIs. In this study, we determined whether the most common on-target resistance mutation for treatment with EGFR-TKI mutation, i.e., the EGFR T790M mutation, can be detected in pre-treatment tissue samples and can predict treatment outcome. We included 33 patients who progressed with a T790M positive relapse upon treatment with EGFR-TKI between 2013 to 2019. Progression-free survival (PFS) time of the single T790M positive patient was 9 months, while the T790M negative patients had a median PFS of 10 months (range 2–27). Our results show that the presence of EGFR T790M mutations in pre-TKI samples is rare, even in patients who subsequently progressed with an EGFR T790M mutation. Abstract EGFR-mutated non-small cell lung cancer (NSCLC) patients can be effectively treated with tyrosine kinase inhibitors (TKI) but frequently present with an EGFR T790M resistance mutation at relapse. We aimed to screen for T790M in pre-treatment formalin-fixed and paraffin-embedded (FFPE) tissue samples of patients with a confirmed T790M mutation at progression. We analyzed 33 pre-treatment DNA samples of NSCLC patients who progressed upon TKI between 2013 to 2019. To establish storage-time dependent formalin fixation-induced background levels for C>T mutations, we analyzed DNA isolated from archival (stored >1 year, n = 22) and recently generated (stored <1 month, n = 11) FFPE samples and included DNA isolated from white blood cells (WBC) (n = 24) as controls. DNA samples were analyzed by droplet digital (dd)PCR, and positivity was defined by outlier detection according to Grubb’s criterion. The T790M background allele frequency levels were 0.160% in DNA isolated from archival-FFPE, 0.100% in fresh FFPE, and 0.035% in WBC. Progression-free survival (PFS) time of the single T790M positive patient was 9 months, while T790M negative patients had a median PFS of 10 months (range 2–27). Proper storage time matched FFPE control samples are essential for reliable detection of T790M mutation at low VAF. The presence of EGFR T790M mutations in pre-TKI samples is rare, even in patients who progressed with EGFR T790M mutations.

Dataset Information

The emergence of T790M mutation in EGFR-mutant lung adenocarcinoma patients having a history of acquired resistance to EGFR-TKI: focus on rebiopsy timing and long-term existence of T790M.

Publications

The emergence of T790M mutation in EGFR-mutant lung adenocarcinoma patients having a history of acquired resistance to EGFR-TKI: focus on rebiopsy timing and long-term existence of T790M.

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