Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer

  • 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.
Author: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
Pubmed Id:
Parent Title (English):Annals of oncology
Publisher:Oxford Univ. Press
Place of publication:Oxford
Document Type:Article
Year of Completion:2018
Date of first Publication:2018/08/23
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/05/20
Tag:ALK-rearranged NSCLC; TP53 mutation status; sequential ALK-inhibitor therapy
Page Number:8
First Page:2068
Last Page:2075
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Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (English):License LogoCreative Commons - Namensnennung-Nicht kommerziell 4.0