Targeted sequencing identifies genetic alterations that confer primary resistance to EGFR tyrosine kinase inhibitor (Korean Lung Cancer Consortium)
| Autor: | Keunchil Park, Jin Seok Ahn, Young Joo Min, Hye Ryun Kim, Eun Kyung Cho, Sun Min Lim, Joo Hang Kim, Hye Cheol Jeong, Myung-Ju Ahn, Ji Hyun Lee, Eun Kyung Kim, Byoung Chul Cho |
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| Rok vydání: | 2016 |
| Předmět: |
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0301 basic medicine Oncology Lung Neoplasms Kaplan-Meier Estimate Bioinformatics medicine.disease_cause Tyrosine-kinase inhibitor tyrosine kinase inhibitor 0302 clinical medicine Epidermal growth factor Carcinoma Non-Small-Cell Lung Prospective Studies Epidermal growth factor receptor Aged 80 and over biology Gefitinib Middle Aged ErbB Receptors epidermal growth factor Treatment Outcome 030220 oncology & carcinogenesis Adenocarcinoma Female KRAS Research Paper medicine.drug Adult medicine.medical_specialty medicine.drug_class 03 medical and health sciences Internal medicine medicine Humans primary resistance Lung cancer Protein Kinase Inhibitors Aged business.industry Cancer Sequence Analysis DNA medicine.disease respiratory tract diseases 030104 developmental biology Drug Resistance Neoplasm Mutation Quinazolines biology.protein next-generation sequencing business |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.8904 |
| Popis: | // Sun Min Lim 1, 2 * , Hye Ryun Kim 1 * , Eun Kyung Cho 3 , Young Joo Min 4 , Jin Seok Ahn 5 , Myung-Ju Ahn 5 , Keunchil Park 5 , Byoung Chul Cho 1 , Ji-Hyun Lee 6 , Hye Cheol Jeong 6 , Eun Kyung Kim 6 , Joo-Hang Kim 2 1 Department of Internal Medicine, Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea 2 Department of Internal Medicine, Division of Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam, Korea 3 Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea 4 Department of Oncology, Asan Medical Center, University of Ulsan college of Medicine, Seoul, Korea 5 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 6 Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea * These authors have contributed equally to this work Correspondence to: Joo-Hang Kim, email: kim123@cha.ac.kr Keywords: primary resistance, epidermal growth factor, next-generation sequencing, tyrosine kinase inhibitor Received: March 01, 2016 Accepted: April 05, 2016 Published: April 21, 2016 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 |
| Databáze: | OpenAIRE |
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