Audit of Molecular Mechanisms of Primary and Secondary Resistance to Various Generations of Tyrosine Kinase Inhibitors in Known Epidermal Growth Factor Receptor-Mutant Non-small Cell Lung Cancer Patients in a Tertiary Centre |
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| Institution: | 1. Molecular Diagnostics, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India;2. Department of Urooncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India;1. Division of Radiation Oncology, Department of Radiology, Juntendo University School of Medicine, Tokyo, Japan;2. Department of Radiation Oncology, Arao Municipal Hospital, Kumamoto, Japan;3. Department of Radiation Oncology, Fujieda Municipal General Hospital, Shizuoka, Japan;4. Department of Radiology, St. Marianna University School of Medicine, Kanagawa, Japan;5. Department of Radiation Oncology, Kyorin University Hospital, Tokyo, Japan;7. Division of Radiation Therapy, Shizuoka Cancer Center, Shizuoka, Japan;11. Radiation Therapy Center, Hitachi Ltd, Hitachinaka General Hospital, Ibaraki, Japan;12. Department of Radiation Oncology, Seirei Mikatahara General Hospital, Shizuoka, Japan;8. Department of Radiation Oncology, Saitama Medical Center, Saitama Medical University, Saitama, Japan;9. Department of Radiation Oncology, Kita-Harima Medical Center, Hyogo, Japan;71. Department of Radiation Oncology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan;112. Department of Radiology, Saitama Medical Center, Dokkyo Medical University, Saitama, Japan;123. Department of Radiology, Nanbu Tokushukai Hospital, Okinawa, Japan;84. Biostatistics Center, Kurume University, Fukuoka, Japan;1. Department of Radiation Oncology, Tenon Hospital, AP-HP, Sorbonne Université, Paris, France;2. Methodology and Quality of Life Unit in Oncology, University Hospital of Besançon, INSERM UMR 1098, Besançon, France;3. Department of Medical Oncology, Hôpital Européen Georges Pompidou, AP-HP, Centre-Université de Paris, Paris, France;4. Department of Medical Oncology, Tenon Hospital, AP-HP, Sorbonne Université, Paris, France;5. Institut Curie, Department of Drug Development and Innovation (D3i), Paris & Saint-Cloud, France;7. Paris-Saclay University, Paris, France;11. Centre de Recherche Saint-Antoine, INSERM UMR_S 938, Saint-Antoine Hospital, Paris, France;12. Institut Universitaire de Cancérologie, Sorbonne Université, Paris, France;1. Department of Nuclear Medicine, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, University of Health Sciences, Ankara, Turkey;2. Department of Nuclear Medicine, Gazi University Faculty of Medicine, Ankara, Turkey;3. Department of General Surgery, Gazi University Faculty of Medicine, Ankara, Turkey;4. Department of Internal Medicine, Division of Medical Oncology, Gazi University Faculty of Medicine, Ankara, Turkey;5. Department of Pathology, Gazi University Faculty of Medicine, Ankara, Turkey;1. Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China;2. Department of Radiation Oncology, People''s Hospital of Guangxi Zhuang Autonomous Region, Nanning, China;3. Department of Neurology, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China;4. Interdisciplinary Institute of Neuroscience and Technology, Zhejiang University Hangzhou, Zhejiang Province, China;5. Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China;7. Department of Radiology, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China;1. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia;2. Department of Cardiothoracic Surgery, The Royal Melbourne Hospital, Melbourne, Victoria, Australia;3. School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia;4. Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia;5. Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia |
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| Abstract: | AimsPresently, three generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are approved against oncogene addicted EGFR-mutant non-small cell lung cancer (NSCLC). Patients with actionable EGFR mutations invariably develop resistance. This resistance can be intrinsic (primary) or acquired (secondary).Materials and methodsThis was a retrospective study carried out between January 2016 and April 2021 analysing 486 samples of NSCLC for primary and secondary resistance to first- (erlotinib, gefitinb), second- (afatinib) and/or third-generation (osimertinib) TKIs in EGFR-mutant NSCLCs by next generation sequencing (NGS). Tissue NGS was carried out using the Thermofischer Ion Torrent? Oncomine? Focus 52 gene assay; liquid biopsy NGS was carried out using the Oncomine Lung Cell-Free Total Nucleic Acid assay. All cases were previously tested for a single EGFR gene with the Therascreen® EGFR RGQ PCR kit.ResultsThe results were divided into four groups: (i) group 1: primary resistance to first- and/or second-generation TKIs. This group, with 21 cases, showed EGFR exon 20 insertions, dual, complex mutations and variant of unknown significance, de novo MET gene amplification besides other mutations. (ii) Group 2: primary resistance to third-generation TKIs. This group showed two cases, with one showing dual EGFR mutation (L858R and E709A) and EGFR gene amplification. (iii) Group 3: secondary resistance to first- and second-generation TKIs. This group had 27 cases, which were previously reported negative for EGFR T790M by single gene testing. Significant findings were MET gene amplification in four cases, with one also showing MET exon 14 skipping mutation. Three cases showed small cell change and one showed loss of primary mutation. (iv) Group 4: secondary resistance to third-generation TKIs. The latter group was further subgrouped into group 4A: secondary resistance to osimertinib (third-generation TKI) when offered as second-line therapy after first- and second-generation TKIs on detection of T790M mutation. This group had 15 cases. EGFR T790M mutation was lost in 10 (10/15; 67%) cases and was retained in five cases. Patients with T790M loss experienced early resistance (6.9 months versus 12.6 months mean, P = 0.0024) compared with cases that retained T790M. Two cases gained MET amplification as the resistance mechanisms. Other mutations that were found when EGFR T790M was lost were in FGFR3, KRAS, PIK3CA, CTNNB1, BRAF genes. One case had EML4-ALK translocation. Two cases showed driver EGFR deletion 19, retained T790M and C797S mutation in Cis form. Group 4B: secondary resistance to osimertinib (when given as first-line therapy) in EGFR-mutant NSCLC. This group had three cases. The duration of osimertinib treatment ranged from 11 to 17 months. Two patients showed additional C797S mutation along with primary EGFR mutation.ConclusionThis study shows the wide spectrum of primary and secondary EGFR resistance mechanisms to first, second and third generation of TKIs and helps us to identify newer therapeutic targets that could carry forward the initial advantage offered by EGFR TKIs. |
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| Keywords: | Afatinib EGFR erlotinib gefitinib next generation sequencing osimertinib resistance |
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