PMID- 27575422
OWN - NLM
STAT- MEDLINE
DCOM- 20171116
LR  - 20220310
IS  - 1556-1380 (Electronic)
IS  - 1556-0864 (Linking)
VI  - 12
IP  - 1
DP  - 2017 Jan
TI  - High Prevalence of Concomitant Oncogene Mutations in Prospectively Identified 
      Patients with ROS1-Positive Metastatic Lung Cancer.
PG  - 54-64
LID - S1556-0864(16)30904-2 [pii]
LID - 10.1016/j.jtho.2016.08.137 [doi]
AB  - OBJECTIVES: Chromosomal rearrangements involving ROS1 define a rare entity of 
      lung adenocarcinomas with exquisite sensitivity to molecularly targeted therapy. 
      We report clinical outcomes and genomic findings of patients with ROS1-positive 
      lung cancer who were prospectively identified within a multiplex biomarker 
      profiling program at the West German Cancer Center. METHODS: Standardized 
      immunohistochemical (IHC) analysis, fluorescence in situ hybridization (FISH), 
      and hotspot mutation analyses were performed in 1345 patients with advanced 
      cancer, including 805 patients with metastatic lung adenocarcinoma. Clinical and 
      epidemiological data were retrieved from the institutional database. RESULTS: 
      ROS1 positivity by IHC analysis was detected in 25 patients with lung cancer 
      (4.8% of lung adenocarcinomas), including 13 patients (2.5%) with ROS1 FISH 
      positivity with a cutoff of at least 15% of events. Of the ROS1 IHC 
      analysis-positive cases, 36% presented with concomitant oncogenic driver 
      mutations involving EGFR (six cases, five of which were clinically validated by 
      response to EGFR-targeting agents), KRAS (two cases), 
      phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene 
      (PIK3CA), and BRAF. Three cases initially classified as ROS1 FISH-negative passed 
      the threshold of 15% positive events when repeat biopsies were analyzed at 
      progression. The median overall survival of the ROS1-positive patients (104 
      months) was significantly superior to that of the 261 patients with 
      EGFR/anaplastic lymphoma kinase/ROS1-negative lung adenocarcinoma (24.4 months, 
      p = 0.044). Interestingly, the overall survival of the 13 ROS1-positive patients 
      with lung cancer from initiation of pemetrexed-based chemotherapy was 
      significantly prolonged when compared with that of 169 pemetrexed-treated 
      patients with EGFR/anaplastic lymphoma kinase/ROS1-negative adenocarcinoma (p = 
      0.01). CONCLUSIONS: ROS1-positive metastatic lung adenocarcinomas frequently 
      harbor concomitant oncogenic driver mutations. Levels of ROS1 FISH-positive 
      events are variable over time. This heterogeneity provides additional therapeutic 
      options if discovered by multiplex biomarker testing and repeat biopsies.
CI  - Copyright (c) 2016 International Association for the Study of Lung Cancer. 
      Published by Elsevier Inc. All rights reserved.
FAU - Wiesweg, Marcel
AU  - Wiesweg M
AD  - Department of Medical Oncology, West German Cancer Center, University Hospital 
      Essen, University Duisburg-Essen, Essen, Germany.
FAU - Eberhardt, Wilfried E E
AU  - Eberhardt WEE
AD  - Department of Medical Oncology, West German Cancer Center, University Hospital 
      Essen, University Duisburg-Essen, Essen, Germany; Division of Thoracic Oncology, 
      West German Lung Center, Ruhrlandklinik, University Hospital Essen, Essen, 
      Germany.
FAU - Reis, Henning
AU  - Reis H
AD  - Institute of Pathology, West German Cancer Center, University Hospital Essen, 
      University Duisburg-Essen, Essen, Germany.
FAU - Ting, Saskia
AU  - Ting S
AD  - Institute of Pathology, West German Cancer Center, University Hospital Essen, 
      University Duisburg-Essen, Essen, Germany.
FAU - Savvidou, Nikoleta
AU  - Savvidou N
AD  - Department of Medical Oncology, West German Cancer Center, University Hospital 
      Essen, University Duisburg-Essen, Essen, Germany.
FAU - Skiba, Charlotte
AU  - Skiba C
AD  - Department of Medical Oncology, West German Cancer Center, University Hospital 
      Essen, University Duisburg-Essen, Essen, Germany.
FAU - Herold, Thomas
AU  - Herold T
AD  - Institute of Pathology, West German Cancer Center, University Hospital Essen, 
      University Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), 
      Partner Site University Hospital Essen, Essen, Germany.
FAU - Christoph, Daniel C
AU  - Christoph DC
AD  - Department of Medical Oncology, West German Cancer Center, University Hospital 
      Essen, University Duisburg-Essen, Essen, Germany.
FAU - Meiler, Johannes
AU  - Meiler J
AD  - Department of Medical Oncology, West German Cancer Center, University Hospital 
      Essen, University Duisburg-Essen, Essen, Germany.
FAU - Worm, Karl
AU  - Worm K
AD  - Institute of Pathology, West German Cancer Center, University Hospital Essen, 
      University Duisburg-Essen, Essen, Germany.
FAU - Kasper, Stefan
AU  - Kasper S
AD  - Department of Medical Oncology, West German Cancer Center, University Hospital 
      Essen, University Duisburg-Essen, Essen, Germany.
FAU - Theegarten, Dirk
AU  - Theegarten D
AD  - Institute of Pathology, West German Cancer Center, University Hospital Essen, 
      University Duisburg-Essen, Essen, Germany.
FAU - Hense, Jorg
AU  - Hense J
AD  - Department of Medical Oncology, West German Cancer Center, University Hospital 
      Essen, University Duisburg-Essen, Essen, Germany.
FAU - Hager, Thomas
AU  - Hager T
AD  - Institute of Pathology, West German Cancer Center, University Hospital Essen, 
      University Duisburg-Essen, Essen, Germany.
FAU - Darwiche, Kaid
AU  - Darwiche K
AD  - Division of Interventional Pneumology, West German Lung Center, Ruhrlandklinik, 
      University Hospital Essen, Essen, Germany.
FAU - Oezkan, Filiz
AU  - Oezkan F
AD  - Division of Interventional Pneumology, West German Lung Center, Ruhrlandklinik, 
      University Hospital Essen, Essen, Germany.
FAU - Aigner, Clemens
AU  - Aigner C
AD  - Division of Thoracic Surgery, West German Lung Center, Ruhrlandklinik, University 
      Hospital Essen, Essen, Germany.
FAU - Welter, Stefan
AU  - Welter S
AD  - Division of Thoracic Surgery, West German Lung Center, Ruhrlandklinik, University 
      Hospital Essen, Essen, Germany.
FAU - Kuhl, Hilmar
AU  - Kuhl H
AD  - Institute for Diagnostic and Interventional Radiology and Neuroradiology, 
      University Hospital Essen, University Duisburg-Essen, Essen, Germany.
FAU - Stuschke, Martin
AU  - Stuschke M
AD  - German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, 
      Germany; Department of Radiotherapy, West German Cancer Center, University 
      Hospital Essen, University Duisburg-Essen, Essen, Germany.
FAU - Schmid, Kurt W
AU  - Schmid KW
AD  - Institute of Pathology, West German Cancer Center, University Hospital Essen, 
      University Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), 
      Partner Site University Hospital Essen, Essen, Germany.
FAU - Schuler, Martin
AU  - Schuler M
AD  - Department of Medical Oncology, West German Cancer Center, University Hospital 
      Essen, University Duisburg-Essen, Essen, Germany; Division of Thoracic Oncology, 
      West German Lung Center, Ruhrlandklinik, University Hospital Essen, Essen, 
      Germany; German Cancer Consortium (DKTK), Partner Site University Hospital Essen, 
      Essen, Germany. Electronic address: martin.schuler@uk-essen.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160827
PL  - United States
TA  - J Thorac Oncol
JT  - Journal of thoracic oncology : official publication of the International 
      Association for the Study of Lung Cancer
JID - 101274235
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Proto-Oncogene Proteins)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (ROS1 protein, human)
SB  - IM
MH  - Adenocarcinoma/*genetics/secondary/therapy
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Biomarkers, Tumor/*genetics
MH  - Combined Modality Therapy
MH  - Female
MH  - Follow-Up Studies
MH  - Gene Rearrangement
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Lung Neoplasms/*genetics/pathology/therapy
MH  - Lymphatic Metastasis
MH  - Male
MH  - Middle Aged
MH  - *Mutation
MH  - Neoplasm Staging
MH  - *Oncogenes
MH  - Prevalence
MH  - Prognosis
MH  - Prospective Studies
MH  - Protein-Tyrosine Kinases/*genetics/metabolism
MH  - Proto-Oncogene Proteins/*genetics/metabolism
MH  - Survival Rate
OTO - NOTNLM
OT  - Concomitant mutations
OT  - EGFR
OT  - Lung adenocarcinoma
OT  - Pemetrexed
OT  - ROS1
EDAT- 2016/08/31 06:00
MHDA- 2017/11/29 06:00
CRDT- 2016/08/31 06:00
PHST- 2016/05/11 00:00 [received]
PHST- 2016/08/17 00:00 [revised]
PHST- 2016/08/18 00:00 [accepted]
PHST- 2016/08/31 06:00 [pubmed]
PHST- 2017/11/29 06:00 [medline]
PHST- 2016/08/31 06:00 [entrez]
AID - S1556-0864(16)30904-2 [pii]
AID - 10.1016/j.jtho.2016.08.137 [doi]
PST - ppublish
SO  - J Thorac Oncol. 2017 Jan;12(1):54-64. doi: 10.1016/j.jtho.2016.08.137. Epub 2016 
      Aug 27.