Clinical Research Papers:

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

Matthias Scheffler, Anne Schultheis, Cristina Teixido, Sebastian Michels, Daniela Morales-Espinosa, Santiago Viteri, Wolfgang Hartmann, Sabine Merkelbach-Bruse, Rieke Fischer, Hans-Ulrich Schildhaus, Jana Fassunke, Martin Sebastian, Monika Serke, Britta Kaminsky, Winfried Randerath, Ulrich Gerigk, Yon-Dschun Ko, Stefan Krüger, Roland Schnell, Achim Rothe, Cornelia Kropf-Sanchen, Lukas Heukamp, Rafael Rosell, Reinhard Büttner and Jürgen Wolf _

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Oncotarget. 2015; 6:10577-10585. https://doi.org/10.18632/oncotarget.3387

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Matthias Scheffler1,2,*, Anne Schultheis1,3,*, Cristina Teixido4, Sebastian Michels1,2, Daniela Morales-Espinosa5, Santiago Viteri6, Wolfgang Hartmann7, Sabine Merkelbach-Bruse1,3, Rieke Fischer1,2, Hans-Ulrich Schildhaus8, Jana Fassunke1,3, Martin Sebastian9, Monika Serke10, Britta Kaminsky11, Winfried Randerath11, Ulrich Gerigk12, Yon-Dschun Ko13, Stefan Krüger14, Roland Schnell15, Achim Rothe16, Cornelia Kropf-Sanchen17, Lukas Heukamp1,3, Rafael Rosell6,18,19, Reinhard Büttner1,3,*, Jürgen Wolf1,2,*

1Center for Integrated Oncology Köln Bonn, Cologne, Germany

2Lung Cancer Group Cologne, Department I for Internal Medicine, University Hospital of Cologne, Cologne, Germany

3Institute of Pathology, University Hospital of Cologne, Cologne, Germany

4Pangaea Biotech, Quirón Dexeus University Hospital, Barcelona, Spain

5Institut d’Investigació en Ciències de la Salut, Germans Trias i Pujol, Badalona, Spain

6Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain

7Gerhard-Domagk-Institute of Pathology, University Hospital of Münster, Münster, Germany

8Institute of Pathology, University Hospital of Göttingen, Göttingen, Germany

9Department of Hematology/Oncology, University Hospital of Frankfurt, Frankfurt, Germany

10Department for Pulmonology and Thoracic Oncology, Lung Clinic Hemer, Hemer, Germany

11Clinic for Pneumology and Allergology Center for Sleep Medicine and Respiratory Care, Bethanien Hospital, Solingen, Germany

12Thoracic Centre, Malteser Hospital Bonn/Rhein-Sieg, Bonn, Germany

13Johanniter Hospital, Evangelical Clinics of Bonn, Bonn, Germany

14Clinic for Pneumology/Allergology/Sleep Medicine and Respiratory Care, Florence-Nightingale-Hospital, Düsseldorf, Germany

15Practice for Internistic Oncology and Hematology, Frechen, Germany

16Practice for Hematology and Oncology Mainka/Dietze/Rothe, Cologne, Germany

17Department II for Internal Medicine, University Hospital of Ulm, Ulm, Germany

18Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain

19Molecular Oncology Research (MORe) Foundation, Barcelona, Spain

*These authors have contributed equally to this work

Correspondence to:

Jürgen Wolf, e-mail: [email protected]

Keywords: non-small cell lung cancer, ROS1, prognosis, chemotherapy, lung cancer

Received: February 11, 2015     Accepted: February 15, 2015     Published: March 25, 2015


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.

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