Targeted sequencing identifies genetic alterations that confer Primary resistance to EGFR tyrosine kinase inhibitor (Korean Lung Cancer Consortium)

Sun Min Lim, Hye Ryun Kim, Eun Kyung Cho, Young Joo Min, Jin Seok Ahn, Myung Ju Ahn, Keunchil Park, ByoungChul Cho, Ji Hyun Lee, Hye Cheol Jeong, Eun Kyung Kim, Joo Hang Kim

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Abstract

Background: Non-small-cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations may exhibit primary resistance to EGFR tyrosine kinase inhibitor (TKI). We aimed to examine genomic alterations associated with de novo resistance to gefitinib in a prospective study of NSCLC patients. Methods: One-hundred and fifty two patients with activating EGFR mutations were included in this study and 136 patients' tumor sample were available for targeted sequencing of genomic alterations in 22 genes using the Colon and Lung Cancer panel (Ampliseq, Life Technologies). Results: All 132 patients with EGFR mutation were treated with gefitinib for their treatment of advanced NSCLC. Twenty patients showed primary resistance to EGFR TKI, and were classified as non-responders. A total of 543 somatic single-nucleotide variants (498 missense, 13 nonsense) and 32 frameshift insertions/deletions, with a median of 3 mutations per sample. TP53 was most commonly mutated (47%) and mutations in SMAD4 was also common (19%), as well as DDR2 (16%), PIK3CA (15%), STK11 (14%), and BRAF (7%). Genomic mutations in the PI3K/Akt/mTOR pathway were commonly found in non-responders (45%) compared to responders (27%), and they had significantly shorter progression-free survival and overall survival compared to patients without mutations (2.1 vs. 12.8 months, P=0.04, 15.7 vs. not reached, P < 0.001). FGFR 1-3 alterations, KRAS mutations and TP53 mutations were more commonly detected in non-responders compared to responders. Conclusion: Genomic mutations in the PI3K/Akt/mTOR pathway were commonly identified in non-responders and may confer resistance to EGFR TKI. Screening lung adenocarcinoma patients with clinical cancer gene test may aid in selecting out those who show primary resistance to EGFR TKI (NCT01697163).

Original languageEnglish
Pages (from-to)36311-36320
Number of pages10
JournalOncotarget
Volume7
Issue number24
DOIs
Publication statusPublished - 2016 Jan 1

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Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Lung Neoplasms
Mutation
Non-Small Cell Lung Carcinoma
Phosphatidylinositol 3-Kinases
Neoplasm Genes
Colonic Neoplasms
Disease-Free Survival
Nucleotides
Prospective Studies
Technology
Survival

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Lim, Sun Min ; Kim, Hye Ryun ; Cho, Eun Kyung ; Min, Young Joo ; Ahn, Jin Seok ; Ahn, Myung Ju ; Park, Keunchil ; Cho, ByoungChul ; Lee, Ji Hyun ; Jeong, Hye Cheol ; Kim, Eun Kyung ; Kim, Joo Hang. / Targeted sequencing identifies genetic alterations that confer Primary resistance to EGFR tyrosine kinase inhibitor (Korean Lung Cancer Consortium). In: Oncotarget. 2016 ; Vol. 7, No. 24. pp. 36311-36320.
@article{2399d1a42a8d44d9b0e318f5c30f53ee,
title = "Targeted sequencing identifies genetic alterations that confer Primary resistance to EGFR tyrosine kinase inhibitor (Korean Lung Cancer Consortium)",
abstract = "Background: Non-small-cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations may exhibit primary resistance to EGFR tyrosine kinase inhibitor (TKI). We aimed to examine genomic alterations associated with de novo resistance to gefitinib in a prospective study of NSCLC patients. Methods: One-hundred and fifty two patients with activating EGFR mutations were included in this study and 136 patients' tumor sample were available for targeted sequencing of genomic alterations in 22 genes using the Colon and Lung Cancer panel (Ampliseq, Life Technologies). Results: All 132 patients with EGFR mutation were treated with gefitinib for their treatment of advanced NSCLC. Twenty patients showed primary resistance to EGFR TKI, and were classified as non-responders. A total of 543 somatic single-nucleotide variants (498 missense, 13 nonsense) and 32 frameshift insertions/deletions, with a median of 3 mutations per sample. TP53 was most commonly mutated (47{\%}) and mutations in SMAD4 was also common (19{\%}), as well as DDR2 (16{\%}), PIK3CA (15{\%}), STK11 (14{\%}), and BRAF (7{\%}). Genomic mutations in the PI3K/Akt/mTOR pathway were commonly found in non-responders (45{\%}) compared to responders (27{\%}), and they had significantly shorter progression-free survival and overall survival compared to patients without mutations (2.1 vs. 12.8 months, P=0.04, 15.7 vs. not reached, P < 0.001). FGFR 1-3 alterations, KRAS mutations and TP53 mutations were more commonly detected in non-responders compared to responders. Conclusion: Genomic mutations in the PI3K/Akt/mTOR pathway were commonly identified in non-responders and may confer resistance to EGFR TKI. Screening lung adenocarcinoma patients with clinical cancer gene test may aid in selecting out those who show primary resistance to EGFR TKI (NCT01697163).",
author = "Lim, {Sun Min} and Kim, {Hye Ryun} and Cho, {Eun Kyung} and Min, {Young Joo} and Ahn, {Jin Seok} and Ahn, {Myung Ju} and Keunchil Park and ByoungChul Cho and Lee, {Ji Hyun} and Jeong, {Hye Cheol} and Kim, {Eun Kyung} and Kim, {Joo Hang}",
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Lim, SM, Kim, HR, Cho, EK, Min, YJ, Ahn, JS, Ahn, MJ, Park, K, Cho, B, Lee, JH, Jeong, HC, Kim, EK & Kim, JH 2016, 'Targeted sequencing identifies genetic alterations that confer Primary resistance to EGFR tyrosine kinase inhibitor (Korean Lung Cancer Consortium)', Oncotarget, vol. 7, no. 24, pp. 36311-36320. https://doi.org/10.18632/oncotarget.8904

Targeted sequencing identifies genetic alterations that confer Primary resistance to EGFR tyrosine kinase inhibitor (Korean Lung Cancer Consortium). / Lim, Sun Min; Kim, Hye Ryun; Cho, Eun Kyung; Min, Young Joo; Ahn, Jin Seok; Ahn, Myung Ju; Park, Keunchil; Cho, ByoungChul; Lee, Ji Hyun; Jeong, Hye Cheol; Kim, Eun Kyung; Kim, Joo Hang.

In: Oncotarget, Vol. 7, No. 24, 01.01.2016, p. 36311-36320.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Targeted sequencing identifies genetic alterations that confer Primary resistance to EGFR tyrosine kinase inhibitor (Korean Lung Cancer Consortium)

AU - Lim, Sun Min

AU - Kim, Hye Ryun

AU - Cho, Eun Kyung

AU - Min, Young Joo

AU - Ahn, Jin Seok

AU - Ahn, Myung Ju

AU - Park, Keunchil

AU - Cho, ByoungChul

AU - Lee, Ji Hyun

AU - Jeong, Hye Cheol

AU - Kim, Eun Kyung

AU - Kim, Joo Hang

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Background: Non-small-cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations may exhibit primary resistance to EGFR tyrosine kinase inhibitor (TKI). We aimed to examine genomic alterations associated with de novo resistance to gefitinib in a prospective study of NSCLC patients. Methods: One-hundred and fifty two patients with activating EGFR mutations were included in this study and 136 patients' tumor sample were available for targeted sequencing of genomic alterations in 22 genes using the Colon and Lung Cancer panel (Ampliseq, Life Technologies). Results: All 132 patients with EGFR mutation were treated with gefitinib for their treatment of advanced NSCLC. Twenty patients showed primary resistance to EGFR TKI, and were classified as non-responders. A total of 543 somatic single-nucleotide variants (498 missense, 13 nonsense) and 32 frameshift insertions/deletions, with a median of 3 mutations per sample. TP53 was most commonly mutated (47%) and mutations in SMAD4 was also common (19%), as well as DDR2 (16%), PIK3CA (15%), STK11 (14%), and BRAF (7%). Genomic mutations in the PI3K/Akt/mTOR pathway were commonly found in non-responders (45%) compared to responders (27%), and they had significantly shorter progression-free survival and overall survival compared to patients without mutations (2.1 vs. 12.8 months, P=0.04, 15.7 vs. not reached, P < 0.001). FGFR 1-3 alterations, KRAS mutations and TP53 mutations were more commonly detected in non-responders compared to responders. Conclusion: Genomic mutations in the PI3K/Akt/mTOR pathway were commonly identified in non-responders and may confer resistance to EGFR TKI. Screening lung adenocarcinoma patients with clinical cancer gene test may aid in selecting out those who show primary resistance to EGFR TKI (NCT01697163).

AB - Background: Non-small-cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations may exhibit primary resistance to EGFR tyrosine kinase inhibitor (TKI). We aimed to examine genomic alterations associated with de novo resistance to gefitinib in a prospective study of NSCLC patients. Methods: One-hundred and fifty two patients with activating EGFR mutations were included in this study and 136 patients' tumor sample were available for targeted sequencing of genomic alterations in 22 genes using the Colon and Lung Cancer panel (Ampliseq, Life Technologies). Results: All 132 patients with EGFR mutation were treated with gefitinib for their treatment of advanced NSCLC. Twenty patients showed primary resistance to EGFR TKI, and were classified as non-responders. A total of 543 somatic single-nucleotide variants (498 missense, 13 nonsense) and 32 frameshift insertions/deletions, with a median of 3 mutations per sample. TP53 was most commonly mutated (47%) and mutations in SMAD4 was also common (19%), as well as DDR2 (16%), PIK3CA (15%), STK11 (14%), and BRAF (7%). Genomic mutations in the PI3K/Akt/mTOR pathway were commonly found in non-responders (45%) compared to responders (27%), and they had significantly shorter progression-free survival and overall survival compared to patients without mutations (2.1 vs. 12.8 months, P=0.04, 15.7 vs. not reached, P < 0.001). FGFR 1-3 alterations, KRAS mutations and TP53 mutations were more commonly detected in non-responders compared to responders. Conclusion: Genomic mutations in the PI3K/Akt/mTOR pathway were commonly identified in non-responders and may confer resistance to EGFR TKI. Screening lung adenocarcinoma patients with clinical cancer gene test may aid in selecting out those who show primary resistance to EGFR TKI (NCT01697163).

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