Genetic Profiling of Non-Small Cell Lung Cancer at Development of Resistance to First- or Second-Generation EGFR-TKIs by CAPP-Seq Analysis of Circulating Tumor DNA

Kohei Otsubo, Kazuko Sakai, Masafumi Takeshita, Daijiro Harada, Koichi Azuma, keiichi ota, Hiroaki Akamatsu, Koichi Goto, Atsushi Horiike, Takayasu Kurata, Noriaki Nakagaki, Kaname Nosaki, Eiji Iwama, Yoichi Nakanishi, Kazuto Nishio, Isamu Okamoto

Research output: Contribution to journalArticle

Abstract

Patients with non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) eventually acquire resistance to these drugs. The identification of various resistance mechanisms for determination of subsequent treatment for these patients will require a method for simultaneous detection of multiple genetic alterations with high sensitivity. We performed cancer personalized profiling by deep sequencing (CAPP-Seq) with circulating tumor DNA obtained from patients with NSCLC who acquired resistance to first- or second-generation EGFR-TKIs. Plasma samples from 27 patients were analyzed, and 24 samples underwent CAPP-Seq successfully. Original activating EGFR mutations were detected in 23 patients, with the remaining patient showing MET amplification. With regard to known mechanisms of EGFR-TKI resistance, the T790M mutation of EGFR was detected in 17 of the 24 patients, MET amplification in 9 patients (6 of whom also harbored T790M), ERBB2 amplification in 2 patients (1 of whom also harbored T790M), and EGFR amplification in 4 patients (all of whom harbored T790M). Our results thus show that CAPP-Seq is applicable to clinical samples for the identification of multiple somatic mutations in circulating tumor DNA obtained from patients with NSCLC at the time of disease progression during treatment with first- or second-generation EGFR-TKIs. Patients positive for the T790M mutation of EGFR were also found to constitute a molecularly heterogeneous population. Key Points: CAPP-Seq is applicable to clinical samples for the identification of multiple somatic mutations. The T790M mutation of EGFR is associated with amplification of MET, ERBB2, or EGFR in NSCLC patients resistant to EGFR-TKIs. T790M-positive patients are molecularly heterogeneous, and genetic alterations coexisting with T790M may differ between patients treated with first-generation or second-generation EGFR-TKIs.

Original languageEnglish
Pages (from-to)1022-1026
Number of pages5
JournalOncologist
Volume24
Issue number8
DOIs
Publication statusPublished - Jan 1 2019

Fingerprint

High-Throughput Nucleotide Sequencing
Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
DNA
Neoplasms
Mutation
Drug Resistance

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Genetic Profiling of Non-Small Cell Lung Cancer at Development of Resistance to First- or Second-Generation EGFR-TKIs by CAPP-Seq Analysis of Circulating Tumor DNA. / Otsubo, Kohei; Sakai, Kazuko; Takeshita, Masafumi; Harada, Daijiro; Azuma, Koichi; ota, keiichi; Akamatsu, Hiroaki; Goto, Koichi; Horiike, Atsushi; Kurata, Takayasu; Nakagaki, Noriaki; Nosaki, Kaname; Iwama, Eiji; Nakanishi, Yoichi; Nishio, Kazuto; Okamoto, Isamu.

In: Oncologist, Vol. 24, No. 8, 01.01.2019, p. 1022-1026.

Research output: Contribution to journalArticle

Otsubo, K, Sakai, K, Takeshita, M, Harada, D, Azuma, K, ota, K, Akamatsu, H, Goto, K, Horiike, A, Kurata, T, Nakagaki, N, Nosaki, K, Iwama, E, Nakanishi, Y, Nishio, K & Okamoto, I 2019, 'Genetic Profiling of Non-Small Cell Lung Cancer at Development of Resistance to First- or Second-Generation EGFR-TKIs by CAPP-Seq Analysis of Circulating Tumor DNA', Oncologist, vol. 24, no. 8, pp. 1022-1026. https://doi.org/10.1634/theoncologist.2019-0101
Otsubo, Kohei ; Sakai, Kazuko ; Takeshita, Masafumi ; Harada, Daijiro ; Azuma, Koichi ; ota, keiichi ; Akamatsu, Hiroaki ; Goto, Koichi ; Horiike, Atsushi ; Kurata, Takayasu ; Nakagaki, Noriaki ; Nosaki, Kaname ; Iwama, Eiji ; Nakanishi, Yoichi ; Nishio, Kazuto ; Okamoto, Isamu. / Genetic Profiling of Non-Small Cell Lung Cancer at Development of Resistance to First- or Second-Generation EGFR-TKIs by CAPP-Seq Analysis of Circulating Tumor DNA. In: Oncologist. 2019 ; Vol. 24, No. 8. pp. 1022-1026.
@article{9fcf145a66f040ec8007b2008ea9f509,
title = "Genetic Profiling of Non-Small Cell Lung Cancer at Development of Resistance to First- or Second-Generation EGFR-TKIs by CAPP-Seq Analysis of Circulating Tumor DNA",
abstract = "Patients with non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) eventually acquire resistance to these drugs. The identification of various resistance mechanisms for determination of subsequent treatment for these patients will require a method for simultaneous detection of multiple genetic alterations with high sensitivity. We performed cancer personalized profiling by deep sequencing (CAPP-Seq) with circulating tumor DNA obtained from patients with NSCLC who acquired resistance to first- or second-generation EGFR-TKIs. Plasma samples from 27 patients were analyzed, and 24 samples underwent CAPP-Seq successfully. Original activating EGFR mutations were detected in 23 patients, with the remaining patient showing MET amplification. With regard to known mechanisms of EGFR-TKI resistance, the T790M mutation of EGFR was detected in 17 of the 24 patients, MET amplification in 9 patients (6 of whom also harbored T790M), ERBB2 amplification in 2 patients (1 of whom also harbored T790M), and EGFR amplification in 4 patients (all of whom harbored T790M). Our results thus show that CAPP-Seq is applicable to clinical samples for the identification of multiple somatic mutations in circulating tumor DNA obtained from patients with NSCLC at the time of disease progression during treatment with first- or second-generation EGFR-TKIs. Patients positive for the T790M mutation of EGFR were also found to constitute a molecularly heterogeneous population. Key Points: CAPP-Seq is applicable to clinical samples for the identification of multiple somatic mutations. The T790M mutation of EGFR is associated with amplification of MET, ERBB2, or EGFR in NSCLC patients resistant to EGFR-TKIs. T790M-positive patients are molecularly heterogeneous, and genetic alterations coexisting with T790M may differ between patients treated with first-generation or second-generation EGFR-TKIs.",
author = "Kohei Otsubo and Kazuko Sakai and Masafumi Takeshita and Daijiro Harada and Koichi Azuma and keiichi ota and Hiroaki Akamatsu and Koichi Goto and Atsushi Horiike and Takayasu Kurata and Noriaki Nakagaki and Kaname Nosaki and Eiji Iwama and Yoichi Nakanishi and Kazuto Nishio and Isamu Okamoto",
year = "2019",
month = "1",
day = "1",
doi = "10.1634/theoncologist.2019-0101",
language = "English",
volume = "24",
pages = "1022--1026",
journal = "Oncologist",
issn = "1083-7159",
publisher = "AlphaMed Press",
number = "8",

}

TY - JOUR

T1 - Genetic Profiling of Non-Small Cell Lung Cancer at Development of Resistance to First- or Second-Generation EGFR-TKIs by CAPP-Seq Analysis of Circulating Tumor DNA

AU - Otsubo, Kohei

AU - Sakai, Kazuko

AU - Takeshita, Masafumi

AU - Harada, Daijiro

AU - Azuma, Koichi

AU - ota, keiichi

AU - Akamatsu, Hiroaki

AU - Goto, Koichi

AU - Horiike, Atsushi

AU - Kurata, Takayasu

AU - Nakagaki, Noriaki

AU - Nosaki, Kaname

AU - Iwama, Eiji

AU - Nakanishi, Yoichi

AU - Nishio, Kazuto

AU - Okamoto, Isamu

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Patients with non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) eventually acquire resistance to these drugs. The identification of various resistance mechanisms for determination of subsequent treatment for these patients will require a method for simultaneous detection of multiple genetic alterations with high sensitivity. We performed cancer personalized profiling by deep sequencing (CAPP-Seq) with circulating tumor DNA obtained from patients with NSCLC who acquired resistance to first- or second-generation EGFR-TKIs. Plasma samples from 27 patients were analyzed, and 24 samples underwent CAPP-Seq successfully. Original activating EGFR mutations were detected in 23 patients, with the remaining patient showing MET amplification. With regard to known mechanisms of EGFR-TKI resistance, the T790M mutation of EGFR was detected in 17 of the 24 patients, MET amplification in 9 patients (6 of whom also harbored T790M), ERBB2 amplification in 2 patients (1 of whom also harbored T790M), and EGFR amplification in 4 patients (all of whom harbored T790M). Our results thus show that CAPP-Seq is applicable to clinical samples for the identification of multiple somatic mutations in circulating tumor DNA obtained from patients with NSCLC at the time of disease progression during treatment with first- or second-generation EGFR-TKIs. Patients positive for the T790M mutation of EGFR were also found to constitute a molecularly heterogeneous population. Key Points: CAPP-Seq is applicable to clinical samples for the identification of multiple somatic mutations. The T790M mutation of EGFR is associated with amplification of MET, ERBB2, or EGFR in NSCLC patients resistant to EGFR-TKIs. T790M-positive patients are molecularly heterogeneous, and genetic alterations coexisting with T790M may differ between patients treated with first-generation or second-generation EGFR-TKIs.

AB - Patients with non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) eventually acquire resistance to these drugs. The identification of various resistance mechanisms for determination of subsequent treatment for these patients will require a method for simultaneous detection of multiple genetic alterations with high sensitivity. We performed cancer personalized profiling by deep sequencing (CAPP-Seq) with circulating tumor DNA obtained from patients with NSCLC who acquired resistance to first- or second-generation EGFR-TKIs. Plasma samples from 27 patients were analyzed, and 24 samples underwent CAPP-Seq successfully. Original activating EGFR mutations were detected in 23 patients, with the remaining patient showing MET amplification. With regard to known mechanisms of EGFR-TKI resistance, the T790M mutation of EGFR was detected in 17 of the 24 patients, MET amplification in 9 patients (6 of whom also harbored T790M), ERBB2 amplification in 2 patients (1 of whom also harbored T790M), and EGFR amplification in 4 patients (all of whom harbored T790M). Our results thus show that CAPP-Seq is applicable to clinical samples for the identification of multiple somatic mutations in circulating tumor DNA obtained from patients with NSCLC at the time of disease progression during treatment with first- or second-generation EGFR-TKIs. Patients positive for the T790M mutation of EGFR were also found to constitute a molecularly heterogeneous population. Key Points: CAPP-Seq is applicable to clinical samples for the identification of multiple somatic mutations. The T790M mutation of EGFR is associated with amplification of MET, ERBB2, or EGFR in NSCLC patients resistant to EGFR-TKIs. T790M-positive patients are molecularly heterogeneous, and genetic alterations coexisting with T790M may differ between patients treated with first-generation or second-generation EGFR-TKIs.

UR - http://www.scopus.com/inward/record.url?scp=85064909078&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064909078&partnerID=8YFLogxK

U2 - 10.1634/theoncologist.2019-0101

DO - 10.1634/theoncologist.2019-0101

M3 - Article

AN - SCOPUS:85064909078

VL - 24

SP - 1022

EP - 1026

JO - Oncologist

JF - Oncologist

SN - 1083-7159

IS - 8

ER -