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. ORCID: 0000-0002-1658-5993, 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.UNSPECIFIEDorcid.org/0000-0002-1658-5993UNSPECIFIED
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: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Department of Biology > Botanical Institute
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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