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Identification of a highly lethal V3+TP53+ subset in ALK+ lung adenocarcinoma

Tyrosine kinase inhibitors (TKI) have improved prognosis in metastatic anaplastic lymphoma kinase (ALK)-driven lung adenocarcinoma, but patient outcomes vary widely. We retrospectively analyzed the clinical course of all cases with assessable baseline TP53 status and/or ALK fusion variant treated at...

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Main Authors: Christopoulos, Petros (Author) , Kirchner, Martina (Author) , Bozorgmehr, Farastuk (Author) , Endris, Volker (Author) , El Sayed, Mei (Author) , Budczies, Jan (Author) , Ristau, Jonas (Author) , Penzel, Roland (Author) , Herth, Felix (Author) , Heußel, Claus Peter (Author) , Eichhorn, Martin E. (Author) , Muley, Thomas (Author) , Meister, Michael (Author) , Rieken, Stefan (Author) , Lasitschka, Felix (Author) , Bischoff, Helge (Author) , Sotillo, Rocio (Author) , Schirmacher, Peter (Author) , Thomas, Michael (Author) , Stenzinger, Albrecht (Author)
Format: Article (Journal)
Language:English
Published: [1 January 2019]
In: International journal of cancer
Year: 2019, Volume: 144, Issue: 1, Pages: 190-199
ISSN:1097-0215
DOI:10.1002/ijc.31893
Online Access:Verlag, Volltext: https://doi.org/10.1002/ijc.31893
Verlag, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.31893
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Author Notes:P. Christopoulos, M. Kirchner, F. Bozorgmehr, V. Endris, M. Elsayed, J. Budczies, J. Ristau, R. Penzel, F.J. Herth, C.P. Heussel, M. Eichhorn, T. Muley, M. Meister, J.R. Fischer, S. Rieken, F. Lasitschka, H. Bischoff, R. Sotillo, P. Schirmacher, M. Thomas, A. Stenzinger
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Summary:Tyrosine kinase inhibitors (TKI) have improved prognosis in metastatic anaplastic lymphoma kinase (ALK)-driven lung adenocarcinoma, but patient outcomes vary widely. We retrospectively analyzed the clinical course of all cases with assessable baseline TP53 status and/or ALK fusion variant treated at our institutions (n = 102). TP53 mutations were present in 17/87 (20%) and the echinoderm microtubule-associated protein-like 4 (EML4)-ALK variant 3 (V3) in 41/92 (45%) patients. The number of metastatic sites at diagnosis was affected more by the presence of V3 than by TP53 mutations, and highest with both factors (mean 5.3, p < 0.001). Under treatment with ALK TKI, progression-free survival (PFS) was shorter with either TP53 mutations or V3, while double positive cases appeared to have an even higher risk (hazard ratio [HR] = 2.9, p = 0.015). The negative effect of V3 on PFS of TKI-treated patients was strong already in the first line (HR = 2.5, p = 0.037) and decreased subsequently, whereas a trend for PFS impairment under first-line TKI by TP53 mutations became stronger and statistically significant only when considering all treatment lines together. Overall survival was impaired more by TP53 mutations (HR = 4.9, p = 0.003) than by V3 (HR = 2.4, p = 0.018), while patients with TP53 mutated V3-driven tumors carried the highest risk of death (HR = 9.1, p = 0.02). Thus, TP53 mutations and V3 are independently associated with enhanced metastatic spread, shorter TKI responses and inferior overall survival in ALK+ lung adenocarcinoma. Both markers could assist selection of cases for more aggressive management and guide development of novel therapeutic strategies. In combination, they define a patient subset with very poor outcome.
Item Description:Die Pluszeichen sind im Titel hochgestellt
First published: 26 September 2018
Gesehen am07.05.2019
Physical Description:Online Resource
ISSN:1097-0215
DOI:10.1002/ijc.31893

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