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., Krueger, 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., Buettner, R. and Wolf, J. (2018). Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer. Ann. Oncol., 29 (10). S. 2068 - 2076. OXFORD: OXFORD UNIV PRESS. ISSN 1569-8041

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Kron, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alidousty, C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheffler, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merkelbach-Bruse, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seidel, D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riedel, R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ihle, M. A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Michels, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nogova, L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fassunke, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heydt, C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kron, F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ueckeroth, F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Serke, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grohe, C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koschel, D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benedikter, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaminsky, B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaaf, B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braess, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sebastian, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kambartel, K. -O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zander, T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schultheis, A. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-169943
DOI: 10.1093/annonc/mdy333
Journal or Publication Title: Ann. Oncol.
Volume: 29
Number: 10
Page Range: S. 2068 - 2076
Date: 2018
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1569-8041
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PD-L1 IMMUNOHISTOCHEMISTRY; SQUAMOUS-CELL; CRIZOTINIB; CHEMOTHERAPY; P53; SURVIVAL; EGFR; INHIBITORS; CERITINIB; MEDICINEMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/16994

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