title: High Prevalence of Concomitant Oncogene Mutations in Prospectively Identified Patients with ROS1-Positive Metastatic Lung Cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: Marcel
authors: M
authors: Wiesweg
authors: 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.
authors: Wilfried E E
authors: WEE
authors: Eberhardt
authors: Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: Henning
authors: H
authors: Reis
authors: Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: Saskia
authors: S
authors: Ting
authors: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: Nikoleta
authors: N
authors: Savvidou
authors: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: Charlotte
authors: C
authors: Skiba
authors: 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.
authors: Thomas
authors: T
authors: Herold
authors: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: Daniel C
authors: DC
authors: Christoph
authors: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: Johannes
authors: J
authors: Meiler
authors: Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: Karl
authors: K
authors: Worm
authors: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: Stefan
authors: S
authors: Kasper
authors: Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: Dirk
authors: D
authors: Theegarten
authors: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: Jörg
authors: J
authors: Hense
authors: Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: Thomas
authors: T
authors: Hager
authors: Division of Interventional Pneumology, West German Lung Center, Ruhrlandklinik, University Hospital Essen, Essen, Germany.
authors: Kaid
authors: K
authors: Darwiche
authors: Division of Interventional Pneumology, West German Lung Center, Ruhrlandklinik, University Hospital Essen, Essen, Germany.
authors: Filiz
authors: F
authors: Oezkan
authors: Division of Thoracic Surgery, West German Lung Center, Ruhrlandklinik, University Hospital Essen, Essen, Germany.
authors: Clemens
authors: C
authors: Aigner
authors: Division of Thoracic Surgery, West German Lung Center, Ruhrlandklinik, University Hospital Essen, Essen, Germany.
authors: Stefan
authors: S
authors: Welter
authors: Institute for Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: Hilmar
authors: H
authors: Kühl
authors: 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.
authors: Martin
authors: M
authors: Stuschke
authors: 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.
authors: Kurt W
authors: KW
authors: Schmid
authors: 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.
authors: Martin
authors: M
authors: Schuler
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000556:secondary / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D015321:Gene Rearrangement; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D009857:Oncogenes; D015995:Prevalence; D011379:Prognosis; D011446:Prospective Studies; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human
keywords: Concomitant mutations; EGFR; Lung adenocarcinoma; Pemetrexed; ROS1