title: The frequency and impact of ROS1 rearrangement on clinical outcomes in never smokers with lung adenocarcinoma.
abstract: BACKGROUND
  To determine the frequency and predictive impact of ROS1 rearrangements on treatment outcomes in never-smoking patients with lung adenocarcinoma.
  
  
  METHODS
  We concurrently analyzed ROS1 and ALK rearrangements and mutations in the epidermal growth factor receptor (EGFR), and KRAS in 208 never smokers with lung adenocarcinoma. ROS1 and ALK rearrangements were identified by fluorescent in situ hybridization.
  
  
  RESULTS
  Of 208 tumors screened, 7 (3.4%) were ROS1 rearranged, and 15 (7.2%) were ALK-rearranged. CD74-ROS1 fusions were identified in two patients using reverse transcriptase-polymerase chain reaction. The frequency of ROS1 rearrangement was 5.7% (6 of 105) among EGFR/KRAS/ALK-negative patients. Patients with ROS1 rearrangement had a higher objective response rate (ORR; 60.0% versus 8.5%; P = 0.01) and a longer median progression-free survival (PFS; not reached versus 3.3 months; P = 0.008) to pemetrexed than those without ROS1/ALK rearrangement. The PFS to EGFR-tyrosine kinase inhibitors in patients harboring ROS1 rearrangement was shorter than those without ROS1/ALK rearrangement (2.5 versus 7.8 months; P = 0.01).
  
  
  CONCLUSIONS
  The frequency of ROS1 rearrangements in clinically selected patients is higher than that reported for unselected patients, suggesting that ROS1 rearrangement is a druggable target in East-Asian never smokers with lung adenocarcinoma. Given the different treatment outcomes to conventional therapies and availability of ROS1 inhibitors, identification of ROS1 rearrangement can lead to successful treatment in ROS1-rearranged lung adenocarcinomas.
authors.affiliation: Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: H R
authors.initials: HR
authors.lastname: Kim
authors.forename: S M
authors.initials: SM
authors.lastname: Lim
authors.forename: H J
authors.initials: HJ
authors.lastname: Kim
authors.forename: S K
authors.initials: SK
authors.lastname: Hwang
authors.forename: J K
authors.initials: JK
authors.lastname: Park
authors.forename: E
authors.initials: E
authors.lastname: Shin
authors.forename: M K
authors.initials: MK
authors.lastname: Bae
authors.forename: S-H I
authors.initials: SH
authors.lastname: Ou
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: S S
authors.initials: SS
authors.lastname: Jewell
authors.forename: D R
authors.initials: DR
authors.lastname: Kang
authors.forename: R A
authors.initials: RA
authors.lastname: Soo
authors.forename: H
authors.initials: H
authors.lastname: Haack
authors.forename: J H
authors.initials: JH
authors.lastname: Kim
authors.forename: H S
authors.initials: HS
authors.lastname: Shim
authors.forename: B C
authors.initials: BC
authors.lastname: Cho
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000077547:Crizotinib; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D000077156:Gefitinib; D005787:Gene Frequency / Q000235:genetics; D015321:Gene Rearrangement / Q000235:genetics; D005971:Glutamates / Q000494:pharmacology / Q000627:therapeutic use; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D000068437:Pemetrexed; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D005971:Glutamates; D000949:Histocompatibility Antigens Class II; C117307:KRAS protein, human; C516714:NVP-TAE684; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D011799:Quinazolines; D011993:Recombinant Fusion Proteins; C045084:invariant chain; D000068437:Pemetrexed; D000077547:Crizotinib; D006147:Guanine; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000077156:Gefitinib
keywords: ROS1; lung adenocarcinoma; never smoker; outcome