Detection of the T790M mutation of EGFR in plasma of advanced non-small cell lung cancer patients with acquired resistance to tyrosine kinase inhibitors (West Japan oncology group 8014LTR study)

Abstract

IntroductionNext-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to overcome resistance to earlier generations of such drugs mediated by a secondary T790M mutation of EGFR, but the performance of a second tumor biopsy to assess T790M mutation status can be problematic.MethodsWe developed and evaluated liquid biopsy assays for detection of TKI-sensitizing and T790M mutations of EGFR by droplet digital PCR (ddPCR) in EGFR mutation–positive non–small cell lung cancer (NSCLC) patients with acquired EGFR-TKI resistance.ResultsA total of 260 patients was enrolled between November 2014 and March 2015 at 29 centers for this West Japan Oncology Group (WJOG 8014LTR) study. Plasma specimens from all subjects as well as tumor tissue or malignant pleural effusion or ascites fluid from 41 patients were collected after the development of EGFR-TKI resistance. All plasma samples were genotyped successfully and the results were reported to physicians within 14 days. TKI-sensitizing and T790M mutations were detected in plasma of 120 (46.2%) and 75 (28.8%) patients, respectively. T790M was detected in 56.7% of patients with plasma positive for TKI-sensitizing mutations. For the 41 patients with paired samples obtained after acquisition of EGFR-TKI resistance, the concordance for mutation detection by ddPCR in plasma compared with tumor tissue or malignant fluid specimens was 78.0% for TKI-sensitizing mutations and 65.9% for T790M.ConclusionsNoninvasive genotyping by ddPCR with cell-free DNA extracted from plasma is a promising approach to the detection of gene mutations during targeted treatment.

EGFR inhibition in NSCLC: New findings…. and opened questions?

“…Interestingly, 18/164 patients with plasma T790M-positive genotyping were T790M-negative on tissue analysis, showing favorable clinical outcomes similar to those of patients with T790M-positive tumor tissue (Oxnard et al, 2016). These data, consistently with those observed in other studies evaluating plasma genotyping approach at the time of PD (Takahama et al, 2016;Thress et al, 2015), demonstrated a lower specificity of plasma-based detection of T790M at PD compared to EGFR-activating mutations detection at baseline, likely due to the higher heterogeneity of TKI-resistant tumors. As single tissue biopsy is just a snapshot of the tumor not reflecting its spatial heterogeneity, ctDNA could be more representative of the overall tumor mutation status, allowing to identify different targetable alterations driving tumor resistance.…”

Rebiopsy of Histological Samples in Pretreated Non-small Cell Lung Cancer: Comparison Among Rebiopsy Procedures

“…Revolutionaly advancement of this non-invasive procedure would raise the convenience and feasibility of rebiopsy. Indeed, liquid biopsy using digital PCR has demonstrated its effectiveness to detect T790M mutation after acquired resistance to EGFR-TKIs (22). Liquid biopsy would compensate for the disadvantages of histological rebiopsy in the near future.…”

Dramatic intracranial response to osimertinib in a poor performance status patient with lung adenocarcinoma harboring the epidermal growth factor receptor T790M mutation: A case report

“…Moreover, absence of brain metastasis has been shown to be associated with prolonged OS in treatment with EGFR-TKIs (17). Recently, a non-invasive approach to the detection of gene mutations using cell-free DNA extracted from the plasma has been developed (18). Novel methods for detecting gene mutations that develop during treatment with EGFR-TKIs are an important aspect of the optimization of personalized therapy.…”