title: Metastatic EML4-ALK fusion detected by circulating DNA genotyping in an EGFR-mutated NSCLC patient and successful management by adding ALK inhibitors: a case report.
abstract: BACKGROUND
  Rebiopsy is highly recommended to identify the mechanism of acquired resistance to EGFR-TKIs in advanced lung cancer. Recent advances in multiplex genotyping based on circulating tumor DNA (ctDNA) provide a strong and non-invasive alternative for detection of the resistance mechanism.
  
  
  METHODS
  Here we report a multiple metastatic NSCLC patient who was detected to have pure EGFR 19 exon deletion (negative for EML4-ALK and ROS1 in both IHC-based and sequencing assay) in the primary lesion and responded to first-line and second-line EGFR-TKI treatments (erlotinib then HY-15772). At 8 months, most lesions remained well controlled except for the liver metastases which presented dramatic progression. Considering the high risk of bleeding in rebiopsy of hepatic lesions, we conducted a multiplex genomic profiling with ctDNA. Results reported coexistence of EGFR mutation and EML4-ALK gene translocation in plasma which heavily indicated that ALK was the primary reason for progression of the liver lesions. This deduction was supported by the repeated response to ALK inhibitors (crizotinib then AP26113) of the hepatic metastases.
  
  
  CONCLUSIONS
  This is the first report of the existence of ALK rearrangement in metastatic lesions in an EGFR mutated patient. It highlighted the feasibility and advantages of using ctDNA multiplex genotyping in identifying the heterogeneity across lesions and the resistance mechanism of targeted treatments.
authors: Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. liangwh@gird.cn.|Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, No. 151, Yanjiang Rd, Guangzhou, 510120, Guangdong Province, PR China. liangwh@gird.cn.
authors: Wenhua
authors: W
authors: Liang
authors: Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. 976091051@qq.com.|Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, No. 151, Yanjiang Rd, Guangzhou, 510120, Guangdong Province, PR China. 976091051@qq.com.
authors: Qihua
authors: Q
authors: He
authors: Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. 1668627198@qq.com.|Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, No. 151, Yanjiang Rd, Guangzhou, 510120, Guangdong Province, PR China. 1668627198@qq.com.
authors: Ying
authors: Y
authors: Chen
authors: Burning Rock Biotechnology Co. Ltd., Guangzhou, China. shannon.chuai@brbiotech.com.
authors: Shaokun
authors: S
authors: Chuai
authors: Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. yinwq88@21cn.com.|Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, No. 151, Yanjiang Rd, Guangzhou, 510120, Guangdong Province, PR China. yinwq88@21cn.com.
authors: Weiqiang
authors: W
authors: Yin
authors: Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. bbmcwei@126.com.|Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, No. 151, Yanjiang Rd, Guangzhou, 510120, Guangdong Province, PR China. bbmcwei@126.com.
authors: Wei
authors: W
authors: Wang
authors: Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. pengguilin@hotmail.com.|Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, No. 151, Yanjiang Rd, Guangzhou, 510120, Guangdong Province, PR China. pengguilin@hotmail.com.
authors: Guilin
authors: G
authors: Peng
authors: Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. caicunzhoudr@163.com.|Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, No. 151, Yanjiang Rd, Guangzhou, 510120, Guangdong Province, PR China. caicunzhoudr@163.com.|Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. caicunzhoudr@163.com.
authors: Caicun
authors: C
authors: Zhou
authors: Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. drjianxing.he@gmail.com.|Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, No. 151, Yanjiang Rd, Guangzhou, 510120, Guangdong Province, PR China. drjianxing.he@gmail.com.
authors: Jianxing
authors: J
authors: He
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D000077547:Crizotinib; D004247:DNA / Q000097:blood / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000097:blood / Q000235:genetics*; D011720:Pyrazoles / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage
chemical_list: C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D004247:DNA; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors