Anna Kron, Christina Alidousty, Matthias Scheffler, Sabine Merkelbach-Bruse, Danila Seidel, Richard Riedel, Michaela A. Ihle, Sebastian Yves Friedrich Michels, Lucia Nogova, Jana Fassunke, Carina Heydt, Florian Kron, Frank Ueckeroth, Monika Serke, Stefan Krüger, Christian Grohé, Dirk Koschel, Josef Benedikter, Britta Kaminsky, Bernhard Schaaf, Jan Braess, Martin Sebastian, Karl-Otto Kambartel, Roman Thomas, Thomas Zander, Anne Maria Schultheis, Reinhard Büttner, Jürgen Wolf
- Background: We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC).
Patients and methods: ALK-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.
Results: Among 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).
Conclusions: In 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.
MetadatenAuthor: | Anna Kron, Christina Alidousty, Matthias Scheffler, Sabine Merkelbach-BruseORCiDGND, Danila Seidel, Richard Riedel, Michaela A. Ihle, Sebastian Yves Friedrich Michels, Lucia Nogova, Jana Fassunke, Carina Heydt, Florian Kron, Frank Ueckeroth, Monika Serke, Stefan Krüger, Christian Grohé, Dirk Koschel, Josef Benedikter, Britta Kaminsky, Bernhard Schaaf, Jan Braess, Martin SebastianORCiDGND, Karl-Otto Kambartel, Roman Thomas, Thomas Zander, Anne Maria Schultheis, Reinhard BüttnerORCiDGND, Jürgen Wolf |
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URN: | urn:nbn:de:hebis:30:3-535663 |
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DOI: | https://doi.org/10.1093/annonc/mdy333 |
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ISSN: | 1569-8041 |
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ISSN: | 0923-7534 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/30165392 |
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Parent Title (English): | Annals of oncology |
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Publisher: | Oxford Univ. Press |
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Place of publication: | Oxford |
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Document Type: | Article |
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Language: | English |
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Year of Completion: | 2018 |
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Date of first Publication: | 2018/08/23 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2020/05/20 |
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Tag: | ALK-rearranged NSCLC; TP53 mutation status; sequential ALK-inhibitor therapy |
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Volume: | 29 |
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Issue: | 10 |
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Page Number: | 8 |
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First Page: | 2068 |
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Last Page: | 2075 |
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Note: | This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
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HeBIS-PPN: | 465004458 |
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Institutes: | Medizin / Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (English): | Creative Commons - Namensnennung-Nicht kommerziell 4.0 |
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