Marcel Wiesweg1, Wilfried E E Eberhardt2, Henning Reis3, Saskia Ting3, Nikoleta Savvidou1, Charlotte Skiba1, Thomas Herold4, Daniel C Christoph1, Johannes Meiler1, Karl Worm3, Stefan Kasper1, Dirk Theegarten3, Jörg Hense1, Thomas Hager3, Kaid Darwiche5, Filiz Oezkan5, Clemens Aigner6, Stefan Welter6, Hilmar Kühl7, Martin Stuschke8, Kurt W Schmid4, Martin Schuler9. 1. Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany. 2. 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. 3. Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany. 4. 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. 5. Division of Interventional Pneumology, West German Lung Center, Ruhrlandklinik, University Hospital Essen, Essen, Germany. 6. Division of Thoracic Surgery, West German Lung Center, Ruhrlandklinik, University Hospital Essen, Essen, Germany. 7. Institute for Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. 8. 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. 9. 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.
Abstract
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.
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.
Authors: Jessica J Lin; Lauren L Ritterhouse; Siraj M Ali; Mark Bailey; Alexa B Schrock; Justin F Gainor; Lorin A Ferris; Mari Mino-Kenudson; Vincent A Miller; Anthony J Iafrate; Jochen K Lennerz; Alice T Shaw Journal: J Thorac Oncol Date: 2017-01-11 Impact factor: 15.609
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Authors: Stefan Kasper; Henning Reis; Sophie Ziegler; Silke Nothdurft; Andre Mueller; Moritz Goetz; Marcel Wiesweg; Jeannette Phasue; Saskia Ting; Sarah Wieczorek; Anna Even; Karl Worm; Michael Pogorzelski; Sandra Breitenbuecher; Johannes Meiler; Andreas Paul; Tanja Trarbach; Kurt Werner Schmid; Frank Breitenbuecher; Martin Schuler Journal: Oncotarget Date: 2017-07-11