Yulong Fu1,2, Anqi Wang1,2, Jieqi Zhou1,2, Wei Feng1, Minhua Shi3, Xiao Xu4, Hongqing Zhao5, Liming Cai6, Jian Feng7, Xuedong Lv8, Xiaodong Zhang9, Wenjing Xu10, Zhengrong Zhang11, Guoer Ma12, Jian Wang13, Tong Zhou14, Dahai Zhao15, Haohui Fang16, Zeyi Liu1,2,17, Jian-An Huang1,2,17. 1. Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China. 2. Suzhou Key Laboratory for Respiratory Diseases, Suzhou, China. 3. Department of Respiratory Medicine, The Second Affiliated Hospital of Soochow University, Suzhou, China. 4. Department of Respiratory Medicine, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China. 5. Department of Respirology, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, China. 6. Department of Respiratory Medicine, Affiliated Hospital of Jiangnan University, Wuxi, China. 7. Department of Respiratory Medicine, Affiliated Hospital of Nantong University, Nantong, China. 8. Department of Respiratory Medicine, The Second Affiliated Hospital of Nantong University, Nantong, China. 9. Department of Medical Oncology, Nantong Tumor Hospital, Nantong, China. 10. Departments of Respiratory Medicine, Northern Jiangsu People's Hospital, Clinical Medical College of Yangzhou University, Yangzhou, China. 11. Department of Respiratory Medicine, First People's Hospital of Yangzhou City, Yangzhou, China. 12. Department of Respiratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China. 13. Department of Respiratory Medicine, Zhenjiang First People's Hospital, Zhenjiang, China. 14. Department of Oncology, Changzhou Cancer Hospital Affiliated to Soochow University, Changzhou, China. 15. Department of Respiratory and Critical Care Medicine, The Second Hospital of Anhui Medical University, Hefei, China. 16. Department of Respiratory Medicine, Anhui Chest Hospital, Hefei, China. 17. Institute of Respiratory Diseases, Soochow University, Suzhou, China.
Abstract
BACKGROUND: Non-small cell lung cancer (NSCLC) patients treated with first-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) almost always acquire resistance, and the development of novel techniques analyzing circulating tumor DNA (ctDNA) have made it possible for liquid biopsy to detect genetic alterations from limited amount of DNA with less invasiveness. While a large amount of patients with EGFR exon 21 p.Thr790 Met (T790M) benefited from osimertinib treatment, acquired resistance to osimertinb has subsequently become a growing challenge. METHODS: We performed tissue and liquid rebiopsy on 50 patients with EGFR-mutant NSCLC who acquired resistance to first-generation EGFR-TKIs. Plasma samples underwent droplet digital PCR (ddPCR) and next-generation sequencing (NGS) examinations. Corresponding tissue samples underwent NGS and Cobas® EGFR Mutation Test v2 (Cobas) examinations. RESULTS: Of the 50 patients evaluated, the mutation detection rates of liquid biopsy group and tissue biopsy group demonstrated no significant differences (41/48, 85.4% vs. 44/48, 91.7%; OR=0.53, 95% CI=0.15 to 1.95). Overall concordance, defined as the proportion of patients for whom at least one identical genomic alteration was identified in both tissue and plasma, was 78.3% (36/46, 95% CI=0.39 to 2.69). Moreover, our results showed that almost half of the patients (46%, 23/50) resistant to first-generation EGFR-TKI harbored p.Thr790 Met (T790M) mutation. 82.6% (19/23) of the T790M positive patients were analyzed by liquid biopsy and 60.9% (14/23) by tumor tissue sequencing. Meanwhile, a wide range of uncommon mutations was detected, and novel mechanisms of osimertinib resistance were discovered. In addition, 16.7% (2/12) of the T790M positive patients with either TP53 R237C or KRAS G12V failed to benefit from the subsequent osimertinib treatment. CONCLUSION: Our results emphasized that liquid biopsy is applicable to analyze the drug resistance mechanisms of NSCLC patients treated with EGFR-TKIs. Moreover, we discovered two uncommon mutations, TP53 R273C and KRAS G12V, which attenuates the effectiveness of osimertinib.
BACKGROUND: Non-small cell lung cancer (NSCLC) patients treated with first-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) almost always acquire resistance, and the development of novel techniques analyzing circulating tumor DNA (ctDNA) have made it possible for liquid biopsy to detect genetic alterations from limited amount of DNA with less invasiveness. While a large amount of patients with EGFR exon 21 p.Thr790 Met (T790M) benefited from osimertinib treatment, acquired resistance to osimertinb has subsequently become a growing challenge. METHODS: We performed tissue and liquid rebiopsy on 50 patients with EGFR-mutant NSCLC who acquired resistance to first-generation EGFR-TKIs. Plasma samples underwent droplet digital PCR (ddPCR) and next-generation sequencing (NGS) examinations. Corresponding tissue samples underwent NGS and Cobas® EGFR Mutation Test v2 (Cobas) examinations. RESULTS: Of the 50 patients evaluated, the mutation detection rates of liquid biopsy group and tissue biopsy group demonstrated no significant differences (41/48, 85.4% vs. 44/48, 91.7%; OR=0.53, 95% CI=0.15 to 1.95). Overall concordance, defined as the proportion of patients for whom at least one identical genomic alteration was identified in both tissue and plasma, was 78.3% (36/46, 95% CI=0.39 to 2.69). Moreover, our results showed that almost half of the patients (46%, 23/50) resistant to first-generation EGFR-TKI harbored p.Thr790 Met (T790M) mutation. 82.6% (19/23) of the T790M positive patients were analyzed by liquid biopsy and 60.9% (14/23) by tumor tissue sequencing. Meanwhile, a wide range of uncommon mutations was detected, and novel mechanisms of osimertinib resistance were discovered. In addition, 16.7% (2/12) of the T790M positive patients with either TP53 R237C or KRAS G12V failed to benefit from the subsequent osimertinib treatment. CONCLUSION: Our results emphasized that liquid biopsy is applicable to analyze the drug resistance mechanisms of NSCLC patients treated with EGFR-TKIs. Moreover, we discovered two uncommon mutations, TP53 R273C and KRAS G12V, which attenuates the effectiveness of osimertinib.
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