TY  - JOUR
A1  - Kron, Anna
A1  - Alidousty, Christina
A1  - Scheffler, Matthias
A1  - Merkelbach-Bruse, Sabine
A1  - Seidel, Danila
A1  - Riedel, Richard
A1  - Ihle, Michaela A.
A1  - Michels, Sebastian Yves Friedrich
A1  - Nogova, Lucia
A1  - Fassunke, Jana
A1  - Heydt, Carina
A1  - Kron, Florian
A1  - Ueckeroth, Frank
A1  - Serke, Monika
A1  - Krüger, Stefan
A1  - Grohé, Christian
A1  - Koschel, Dirk
A1  - Benedikter, Josef
A1  - Kaminsky, Britta
A1  - Schaaf, Bernhard
A1  - Braess, Jan
A1  - Sebastian, Martin
A1  - Kambartel, Karl-Otto
A1  - Thomas, Roman
A1  - Zander, Thomas
A1  - Schultheis, Anne Maria
A1  - Büttner, Reinhard
A1  - Wolf, Jürgen
T1  - Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer
T2  - Annals of oncology
N2  - 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.
KW  - ALK-rearranged NSCLC
KW  - sequential ALK-inhibitor therapy
KW  - TP53 mutation status
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/53566
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-535663
SN  - 1569-8041
SN  - 0923-7534
N1  - 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
VL  - 29
IS  - 10
SP  - 2068
EP  - 2075
PB  - Oxford Univ. Press
CY  - Oxford
ER  -