ROS1 rearrangements in lung adenocarcinoma: prognostic impact, therapeutic options and genetic variability

// Matthias Scheffler 1, 2, * , Anne Schultheis 1, 3, * , Cristina Teixido 4 , Sebastian Michels 1, 2 , Daniela Morales-Espinosa 5 , Santiago Viteri 6 , Wolfgang Hartmann 7 , Sabine Merkelbach-Bruse 1, 3 , Rieke Fischer 1, 2 , Hans-Ulrich Schildhaus 8 , Jana Fassunke 1, 3 , Martin Sebastian 9 , Monika Serke 10 , Britta Kaminsky 11 , Winfried Randerath 11 , Ulrich Gerigk 12 , Yon-Dschun Ko 13 , Stefan Krüger 14 , Roland Schnell 15 , Achim Rothe 16 , Cornelia Kropf-Sanchen 17 , Lukas Heukamp 1, 3 , Rafael Rosell 6, 18, 19 , Reinhard Büttner 1, 3, * , Jürgen Wolf 1, 2, * 1 Center for Integrated Oncology Köln Bonn, Cologne, Germany 2 Lung Cancer Group Cologne, Department I for Internal Medicine, University Hospital of Cologne, Cologne, Germany 3 Institute of Pathology, University Hospital of Cologne, Cologne, Germany 4 Pangaea Biotech, Quirón Dexeus University Hospital, Barcelona, Spain 5 Institut d’Investigació en Ciències de la Salut, Germans Trias i Pujol, Badalona, Spain 6 Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain 7 Gerhard-Domagk-Institute of Pathology, University Hospital of Münster, Münster, Germany 8 Institute of Pathology, University Hospital of Göttingen, Göttingen, Germany 9 Department of Hematology/Oncology, University Hospital of Frankfurt, Frankfurt, Germany 10 Department for Pulmonology and Thoracic Oncology, Lung Clinic Hemer, Hemer, Germany 11 Clinic for Pneumology and Allergology Center for Sleep Medicine and Respiratory Care, Bethanien Hospital, Solingen, Germany 12 Thoracic Centre, Malteser Hospital Bonn/Rhein-Sieg, Bonn, Germany 13 Johanniter Hospital, Evangelical Clinics of Bonn, Bonn, Germany 14 Clinic for Pneumology/Allergology/Sleep Medicine and Respiratory Care, Florence-Nightingale-Hospital, Düsseldorf, Germany 15 Practice for Internistic Oncology and Hematology, Frechen, Germany 16 Practice for Hematology and Oncology Mainka/Dietze/Rothe, Cologne, Germany 17 Department II for Internal Medicine, University Hospital of Ulm, Ulm, Germany 18 Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain 19 Molecular Oncology Research (MORe) Foundation, Barcelona, Spain * These authors have contributed equally to this work Correspondence to: Jürgen Wolf, e-mail: juergen.wolf@uk-koeln.de Keywords: non-small cell lung cancer, ROS1, prognosis, chemotherapy, lung cancer Received: February 11, 2015      Accepted: February 15, 2015      Published: March 25, 2015 ABSTRACT Background: While recent data show that crizotinib is highly effective in patients with ROS1 rearrangement, few data is available about the prognostic impact, the predictive value for different treatments, and the genetic heterogeneity of ROS1 -positive patients. Patients and Methods: 1137 patients with adenocarcinoma of the lung were analyzed regarding their ROS1 status. In positive cases, next-generation sequencing (NGS) was performed. Clinical characteristics, treatments and outcome of these patients were assessed. Overall survival (OS) was compared with genetically defined subgroups of ROS1 -negative patients. Results: 19 patients of 1035 evaluable (1.8%) had ROS1 -rearrangement. The median OS has not been reached. Stage IV patients with ROS1 -rearrangement had the best OS of all subgroups (36.7 months, p < 0.001). 9 of 14 (64.2%) patients had at least one response to chemotherapy. Estimated mean OS for patients receiving chemotherapy and crizotinib was 5.3 years. Ten patients with ROS1 -rearrangement (52.6%) harbored additional aberrations. Conclusion: ROS1 -rearangement is not only a predictive marker for response to crizotinib, but also seems to be the one of the best prognostic molecular markers in NSCLC reported so far. In stage IV patients, response to chemotherapy was remarkable high and overall survival was significantly better compared to other subgroups including EGFR -mutated and ALK -fusion-positive NSCLC.