Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer
Open accessAbstract
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.
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TP53 co-mutations are an independent negative prognostic factor in ALK-rearranged LUAD regardless of systemic therapy type.
“are an independent negative prognostic factor in ALK-re-arrangement-positive LUAD, regardless of the type of systemic therapy used128–130.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [129]
TP53 co-mutations promote genomic instability in ALK-rearranged LUAD.
“TP53 co-mutations promote genomic instability”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [129]
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Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy
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- Authors
- Kron, A., Alidousty, C., Scheffler, M., Merkelbach-Bruse, S., Seidel, D., Riedel, R., Ihle, M. A., Michels, S., Nogova, L., Fassunke, J., Heydt, C., Kron, F., Ueckeroth, F., Serke, M., Krüger, S., Grohe, C., Koschel, D., Benedikter, J., Kaminsky, B., Schaaf, B., Braess, J., Sebastian, M., Kambartel, K. O., Thomas, R., Zander, T., Schultheis, A. M., Büttner, R., & Wolf, J.
- Affiliations
- University Hospital Cologne (DE)
- University of Cologne (DE)
- Centrum für Integrierte Onkologie (DE)
- Lungenklinik Hemer (DE)
- München Klinik Bogenhausen (DE)
- Krankenhaus Bethanien (DE)
- Klinikum Dortmund (DE)
- Krankenhaus Barmherzige Brüder (DE)
- Goethe University Frankfurt (DE)
- Bethanien Krankenhaus Moers (DE)
- Corresponding author
- Wolf, J.
- ORCID
- Venue
- Annals of Oncology
- Publisher
- Elsevier BV
- Published
- 2018-10
- Volume
- 29
- Issue
- 10
- Pages
- 2068-2075
- ISSN
- 0923-7534 (ISSN-L)
- PMC
- PMC6225899
- OpenAlex
- W2889170871
- Cited by
- 197
- References
- 37
- Citations by year
- 2026: 13 · 2025: 13 · 2024: 23 · 2023: 31 · 2022: 30 · 2021: 30 · 2020: 36 · 2019: 17 · 2018: 4
- FWCI
- 16.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Annals of Oncology (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by-nc)
- Funders
- Amgen
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- Celgene
- Grifols
- Chugai Pharmaceutical
- Ignyta
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- ALK rearrangement, non-small cell lung cancer, co-occurring mutations, crizotinib, ALK inhibitors, progression-free survival, overall survival, chemotherapy, prognostic factors, targeted therapy resistance, next-generation sequencing, fluorescence in situ hybridization
- MeSH terms
- Anaplastic Lymphoma Kinase, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Female, Follow-Up Studies, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Prognosis, Gene Rearrangement, Cohort Studies, Survival Rate, Tumor Suppressor Protein p53, Carcinoma, Adenosquamous, Young Adult
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