title: The molecular detection and clinical significance of ALK rearrangement in selected advanced non-small cell lung cancer: ALK expression provides insights into ALK targeted therapy.
abstract: BACKGROUND
  This study aimed to elucidate clinical significance of anaplastic lymphoma kinase (ALK) rearrangement in selected advanced non-small cell lung cancer (NSCLC), to compare the application of different ALK detection methods, and especially evaluate a possible association between ALK expression and clinical outcomes in crizotinib-treated patients.
  
  
  METHODS
  ALK status was assessed by fluorescent in situ hybridization (FISH), immunohistochemistry (IHC) and quantitative RT-PCR (qRT-PCR) in 173 selected advanced NSCLC patients. Clinicopathologic data, genotype status and survival outcomes were analyzed. Moreover, the association of ALK expression with clinical outcomes was evaluated in ALK FISH-positive crizotinib-treated patients including two patients with concurrent epidermal growth factor receptor (EGFR) mutation.
  
  
  RESULTS
  The positivity detection rate of ALK rearrangement by FISH, IHC and qRT-PCR was 35.5% (59/166), 35.7% (61/171), and 27.9% (34/122), respectively. ALK rearrangement was observed predominantly in young patients, never or light smokers, and adenocarcinomas, especially with signet ring cell features and poor differentiation. Median progression-free survival (PFS) of crizotinib-treated patients was 7.6 months. The overall survival (OS) of these patients was longer compared with that of crizotinib-naive or wild-type cohorts, but there was no significant difference in OS compared with patients with EGFR mutation. ALK expression did not associate with PFS; but, when ALK expression was analyzed as a dichotomous variable, moderate and strong ALK expression had a decreased risk of death (P = 0.026). The two patients with concomitant EGFR and ALK alterations showed difference in ALK expression, response to EGFR and ALK inhibitors, and overall survival.
  
  
  CONCLUSIONS
  Selective enrichment according to clinicopathologic features in NSCLC patients could highly improve the positivity detection rate of ALK rearrangement for ALK-targeted therapy. IHC could provide more clues for clinical trial design and therapeutic strategies for ALK-positive NSCLC patients including patients with double genetic aberration of ALK and EGFR.
authors.affiliation: Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.
authors.forename: Ning-Ning
authors.initials: NN
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.
authors.forename: Yu-Tao
authors.initials: YT
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.
authors.forename: Xue-Zhi
authors.initials: XZ
authors.lastname: Hao
authors.affiliation: Department of Pathology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Department of Pathology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Lin
authors.affiliation: Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.
authors.forename: Yu-Jie
authors.initials: YJ
authors.lastname: Zhou
authors.affiliation: Department of Medical Record, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Han
authors.affiliation: Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.
authors.forename: Yuankai
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D000077547:Crizotinib; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D011995:Recombination, Genetic; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases