Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer |
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| Institution: | 1. Network Genomic Medicine, Cologne, Germany;2. Lung Cancer Group Cologne, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany;3. Center for Integrated Oncology Köln Bonn, Cologne, Germany;4. Institute of Pathology, University Hospital of Cologne, Cologne, Germany;5. CECAD Cluster of Excellence, University of Cologne, Cologne, Germany;6. Department of Pneumology, Lungenklinik Hemer des Deutschen Gemeinschafts-Diakonieverbandes GmbH, Hemer, Germany;7. Department of Pneumology, Florence Nightingale Hospital, Düsseldorf, Germany;8. Department of Pneumology, Evangelische Lungenklinik Berlin (Paul Gerhardt Diakonie), Berlin, Germany;9. Department of Pneumology, Fachkrankenhaus Coswig, Coswig, Germany;10. Department of Pneumology, Klinikum Bogenhausen, Munich, Germany;11. Department of Pneumology, Krankenhaus Bethanien, Solingen, Germany;12. Lung Cancer Center, Klinikum Dortmund GmbH, Dortmund, Germany;13. Department of Oncology and Hematology, Krankenhaus Barmherzige Brueder, Regensburg, Germany;14. Department of Oncology and Hematology, University Hospital Frankfurt (Johannes-Wolfgang Goethe Institute), Frankfurt am Main, Germany;15. Department of Pneumology, Bethanien Hospital Moers-Lungenzentrum, Moers, Germany;16. Cologne Center for Genomics, University Hospital of Cologne, Cologne, Germany |
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| Abstract: | BackgroundWe analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC).Patients and methodsALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders.ResultsAmong 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients PFS 3.9 months (95% CI: 2.4–5.6) versus 10.3 months (95% CI: 8.6–12.0), P < 0.001; OS 15.0 months (95% CI: 5.0–24.9) versus 50.0 months (95% CI: 22.9–77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only PFS first-line chemotherapy 2.6 months (95% CI: 1.3–4.1) versus 6.2 months (95% CI: 1.8–10.5), P = 0.021; OS 2.0 months (95% CI: 0.0–4.6) versus 9.0 months (95% CI: 6.1–11.9), P = 0.035], crizotinib plus chemotherapy PFS crizotinib 5.0 months (95% CI: 2.9–7.2) versus 14.0 months (95% CI: 8.0–20.1), P < 0.001; OS 17.0 months (95% CI: 6.7–27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor PFS next-generation inhibitor 5.4 months (95% CI: 0.1–10.7) versus 9.9 months (95% CI: 6.4–13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001).ConclusionsIn ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup. |
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